Compounds, process for obtaining the compounds, pharmaceutical composition, use of the compounds and method for treating psychiatric disorders and/or sleep disorders

ABSTRACT

The present disclosure relates to novel and inventive pharmacologically active benzimidazole derivative compounds, which surprisingly have high affinity for melatonin MT1 and MT2 receptors and low affinity for CYP450 complex enzymes, specially CYP1A2. The present invention also relates to novel and inventive routes of synthesis of these compounds, pharmaceutical compositions comprising the compounds and the use of these compounds in the treatment of individuals affected by psychiatric disorders and/or sleep disorders related to these receptors (specially depression, anxiety, circadian cycle disorders), in addition to a process for producing the composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No.16/344,721, having a filing date of Apr. 24, 2019, which was a 371application of International application PCT/BR2017/050320, filed Oct.23, 2017, which claimed the benefit of Brazilian applicationBR1020160248140, filed Oct. 24, 2016, all of said applicationsincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel and inventive pharmacologicallyactive benzimidazole derivative compounds, which have affinity formelatonergic receptors, specially MT1 and MT2, showing highbioavailability and decreased drug-drug interaction potential. Novel andinventive routes of synthesis are also described for these compounds, aswell as pharmaceutical compositions comprising these compounds and theiruse in the treatment of individuals affected by psychiatric disordersand/or sleep disorders related to such receptors, such as depression,anxiety, insomnia and circadian cycle disorders. The present inventionis in the field of pharmacy, medicine and chemistry.

BACKGROUND OF THE INVENTION

According to the World Health Organization (WHO) estimates, over 350million people worldwide suffer from depression. According to thisestimate, depression is common in every region of the world and it isrelated to social, psychological and biological factors, and may beassociated with other disorders such as anxiety and sleep disorders. Theearlier a treatment for these disorders is started, the more efficientit is. From the biological stand point, several treatments are now beingused and each of them has advantages and disadvantages, as describedbelow.

One of the treatments for psychiatric disorders and sleep disorders isthe simulation of the physiological effects of melatonin. Melatonin is anatural hormone widely present in a variety of organisms, such asbacteria, unicellular algae, fungi, plants, vertebrates and mammals,including humans. In mammals, melatonin is mainly produced by the pinealgland and released into the blood stream following the circadian rhythm,reaching a high plasma concentration at night (Zlotos, D. P., Jockers,R., Cecon, E., Rivara, S., & Witt-Enderby, P. A. (2014). MT1 and MT2melatonin receptors: ligands, models, oligomers, and therapeuticpotential. Journal of Medicinal Chemistry, 57(8), 3161-3185).

The physiological effects of melatonin are mediated by the activation ofG protein-coupled melatonergic receptors, which have been named MT₁ andMT₂. Both receptors are present in mammals, including humans. Melatoninhas a variety of activities, including chronobiotic, hypnotic,antioxidative, oncostatic, immunoregulatory activities and it is alsolinked to the reproductive cycle management, controlling the onset ofpuberty. Its contribution in the regulation of human mood and behaviorhas arisen significant clinical attention. Deficiencies in melatoninproduction or in the expression of its receptors, as well as changes inrhythm and range of melatonin secretion, have shown importance in breastcancer, neurodegenerative diseases and in Parkinson's and Alzheimer'sdiseases, in addition to some neurological disorders in children,conditions such as chronic insomnia and sleep disorders related to thecircadian cycle. However, although widely available, commercialmelatonin has an unfavorable pharmacokinetic profile due to its highfirst pass metabolism, very short half-life and high pharmacokineticinter-individual variability.

Recently, the implication of melatonin in neuropsychiatric disorders,such as major depressive disorder, has arisen special attention due tothe development of the molecule agomelatine, a melatonergic agonist thattargets MT1 and MT2 receptors. (V. Srinivasan, Amnon Brzezinski,SukruOter and Samuel D. Shillcutt, in Melatonin and Melatonergic Drugsin Clinical Practice-2014^(th) Ed.-pg. v).

Agomelatine and ramelteon are two examples of commercially availablemelatonergic compounds; although considered effective, presentnon-optimal pharmacokinetics for oral drugs, as explained below.Agomelatine, described in the document EP 0 447 285 by Andrieux et al.describes compounds of general formula:

which are useful in the treatment of central nervous system diseases.Similarly, U.S. Pat. No. 6,034,239 by Ohkawa et al. describes ramelteonas part of the compounds of general formula:

wherein R1 is an optionally substituted hydrocarbon group, an optionallysubstituted amino group or an optionally substituted heterocyclic group;R2 represents a hydrogen or an optionally substituted hydrocarbon group;R3 represents a hydrogen atom, an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group; X representsCHR4, NR4, O or S, wherein R4 represents a hydrogen atom or anoptionally substituted hydrocarbon group; Y is C, CH or N, provided thatwhen X is CH2, Y is C or CH; the dashed line represents a single ordouble bond; A represents an optionally substituted 5- to 7-memberedoxygen-containing heterocyclic ring; ring B represents an optionallysubstituted benzene ring and m represents a full figure from 1 to 4.

Agomelatine and ramelteon have appropriate oral absorption. However,both compounds undergo extensive hepatic (or first pass) metabolism,resulting in low absolute bioavailabilities, which are estimated to be1% for agomelatine and 1.8% for ramelteon (respectively:Valdoxan-Product Information-Australia, and Pandi-Perumal et al.,Pharmacotherapy of insomnia with ramelteon: safety, efficacy andclinical applications, Journal of Central Nervous System Disease 2011,3, 51-65). The low bioavailability due to extensive metabolism leads tohighly variable pharmacokinetic profiles for both drugs amongindividuals. The main metabolite of ramelteon, which is characterized byhydroxylation of the secondary carbon in the R1 group, is also activeand, therefore, the action of the drug depends on its metabolism, whichcompromises drug efficacy due to the population heterogeneity.

Bioavailability is one of the most important properties in oral drugs. Ahigh oral bioavailability allows a reduction in dose, enough to achieveproper pharmacological effect, reducing the risk of side effects andtoxicity. A low bioavailability may result in low efficacy and highinter-individual variability, which may trigger unpredictable responsesto the drug.

Therefore, if we only consider the unmet need for new drugs forpsychiatric disorders and/or sleep disorders along with thebioavailability problems already described for the commerciallyavailable melatonergic agonists, it is possible to observe the need fordevelopment of new drugs that overcome these disadvantages. In addition,some melatonergic agonists, such as agomelatine, show additionaldisadvantages specially in relation to drug interaction andhepatotoxicity, as explained below.

Agomelatine tends to interact with proteins naturally involved with themetabolism of xenobiotic compounds, such as liver cytochrome enzymes(CYP450). Around 90% of agomelatine is metabolized in the liver by theP450 cytochrome 1A2 (CYP1A2) enzyme and 10% by cytochromes CYP2C9 andCYP2C19, with a high first pass metabolism, as previously mentioned. Onepossible metabolite of agomelatine is 3,4-epoxide, which is highlyreactive and can covalently modify important proteins, probably beingresponsible for liver toxicity.

As it is a CYP1A2 substrate, the concomitant administration ofagomelatine with other drugs that interact with this isoform (such asfluvoxamine and ciprofloxacin) is not recommended, as described in thepackage leaflet for the reference drug for agomelatine, Valdoxan. Sincethese drugs are potent inhibitors of CYP1A2, their concomitantadministration with agomelatine inhibits its metabolism and may lead toelevated plasma concentrations.

According to a recent statement issued by the European Medicine Agency(EMA), other drugs that are moderate inhibitors of CYP1A2, such aspropranolol, and CYP1A2 inducers, such as rifampicin, also should not beadministered concomitantly with agomelatine since they alter itsmetabolism, which may lead to liver toxicity (especially in the case ofinducers). In addition, the fact that agomelatine metabolism isdependent on CYP2C9 and CYP2C19, two highly polymorphic proteins in thepopulation, makes the metabolism of this drug highly variable inpatients, which leads to an additional risk.

Thus, there is an evident need for the development of new drugs thatovercome agomelatine bioavailability issues, and are also capable ofreducing potential adverse effects related to liver metabolism.Therefore, there is a great interest in the development of syntheticmolecules targeting the melatonergic system and that are more suitablefor patients. Particularly, drugs from this class that do not interactwith CYP enzymes, specially CYP1A2, would provide therapeutic and safetyadvantages for patients. (Mor, M. et al. Recent advances in thedevelopment of melatonin MT(1) and MT(2) receptor agonists. ExpertOpinion on Therapeutic Patents 2010, 20(8), 1059-1077).

In the state of the art, several melatonin receptor ligands fromdifferent structural classes are described and will be mentioned hereonly as reference of the state of the art, since none of them show theadvantages of the present invention.

Several of these ligands have been designed comprising the bicyclicindole ring substitution present in melatonin with other bicyclic ornon-bicyclic bioisosteric rings, such as naphthalene, benzofuran,benzothiophene, benzoxazole, indane, tetralin, quinoline, phenyl, amongmany others, without considerable detriment to the high affinity toreceptors. The wide variety of the bioisosteric indole nuclei describedin the state of the art seems to indicate that the nature of thearomatic ring type of different ligands is less relevant for theaffinity with melatonin receptors.

An exception to this rule is observed when the bicyclic nucleus of theligand, e.g. melatonin indolic nucleus, is substituted by abenzimidazole nucleus. In this case, a decrease in the affinity for themelatonergic receptors is observed in comparison to ligands comprisingother nuclei (Zlotos, DP, Jockers, R., Cecon, E., Rivara, S., &Witt-Enderby, P A,-MT1 and MT2 melatonin receptors: ligands, models,oligomers, and therapeutic potential Journal of Medicinal Chemistry, 57(8), 3161-3185 Zlotos, DP (2005) Recent advances in melatonin receptorligands Archiv Der Pharmazie (Weinheim), 338(5-6), 229-247; Cathy D.Mahle, Katherine S. Takaki and A. John Watson in Annual Reports inMedicinal Chemistry vol. 32, pg. 36 e Melatonin and Melatonergic Drugsin Clinical Practice-V. Srinivasan, Amnon Brzezinski, SukruOter andSamuel D. Shillcutt, 2014th Ed.-pg. 99).

Although many compounds with high affinity for melatonin receptors havebeen described to date, references of compounds which have affinity andwhich show a benzimidazole type bicyclic ring as central nucleus areremarkably rare. The main references related to derivatives containing abenzimidazole nucleus are described below.

In U.S. Pat. No. 5,276,051, along with its divisions U.S. Pat. Nos.5,308,866 and 5,380,750, Lesieur et al. describe melatonin agonistcompounds comprising various types of bicyclic rings, among them,indole, benzothiophene, benzimidazole, benzoisoxazole, benzoisothiazoleand indazole. In this document, the compound shown in example 57 isN-[2-(6-methoxybenzimidazol-1-yl)-ethyl]acetamide, corresponding to themelatonin analogue in which the indole nucleus is substituted bybenzimidazole. Although this document does not disclose detailedinformation regarding affinity for the described compounds, the affinityof the compound in example 57 was published in a later study, wheredifferent melatonin analogs were analyzed for their affinities. Underassay conditions, the affinity of this benzimidazole derivative wasfound to be approximately 3,200 times lower than melatonin affinity(Depreux, P., Lesieur, D., Mansour, H. A., Morgan, P., Howell, H. E.,Renard, P., et al. (1994) Synthesis and Structure-Activity Relationshipsof Novel Naphthalene and Bioisosteric Related Amidic Derivatives asMelatonin Receptor Ligands Journal of Medicinal Chemistry, 37 (20),3231-3239; P. A. Witt-Enderby, P-K. Li, Vitamin and Hormones, 2000, 58,321-354).

Depreux et al (Synthetic Communications 1994, 24 (15), 2123-2132)describe melatonin-like benzimidazole compounds that were also describedin U.S. Pat. No. 5,260,051. Among synthesized compounds, it is theabovementioned benzimidazole analogue of melatonin. In this document, nodata regarding the affinities of these compounds to melatonin receptorsare reported.

In U.S. Pat. No. 5,496,826 are described compounds of formula:

wherein R═H or C1-4 alkoxy; X═CH or N; y=NH, 0 or S; Z═C1-4 alkyl, C3-6cycloalkyl, C2-3 alkenyl, NH2, C1-4 alkylamino, or C1-4 alkoxyalkyl,except that Z cannot be CH3 when R═H, X═CH and y=NH and Z cannot be CH3when R═H, X═N and y=NH and NHC(O)Z is in the “para” position. Among thedisclosed compounds are benzimidazoles with anticonvulsive properties.

Other examples of melatonergic compounds that do not containbenzimidazole nuclei and therefore are not relevant to the presentinvention, are mentioned as state of the art and can be found in: EP 0506 539, WO 1997/11056, WO99/62515, WO95/17405, U.S. Pat. Nos.5,856,529, 6,211,225.

However, all compounds described in the state of the art usually do nothave good affinity to melatonergic receptors, making them less suitablefor therapeutic use.

Thus, the present invention addresses this gap with novel compoundscomprising benzimidazole nucleus with novel and inventive substituents.In these compounds, the carbon between the nitrogen of the benzimidazolering is bonded to an oxygen or sulfur atom, followed by an alkyl chain.These compounds have high affinity for the melatonergic receptors MT1and MT2 and have low affinity for the CYP450 complex enzymes. Thus,these compounds show a promising pharmacokinetic profile, with highbioavailability; additionally, it is possible to avoid liver problems,including those resulting from drug interactions. The compounds of thepresent invention are useful in the treatment of subjects affected withpsychiatric disorders and/or sleep disorders mediated by or associatedwith these receptors, such as disorders related to sleep and circadiancycle, jet lag, chronic insomnia and/or psychiatric disorders such asmajor depressive disorder, seasonal depression, and anxiety.

Based on a literature survey, no documents were found anticipating orsuggesting the findings of the present invention, so that the technicalsolution here proposed has novelty and inventive activity compared tothe state of the art.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to novel and inventivepharmacologically active benzimidazole derivative compounds with highbioavailability and reduced drug-drug interaction effects. Morespecifically, they have high affinity for melatonin MT1 and MT2receptors and have no affinity for CYP enzymes, specially CYP1A2. Themethod for obtaining the route of synthesis for these compounds,pharmaceutical compositions and their use in the treatment ofindividuals affected with psychiatric disorders and/or sleep disordersare also described.

Therefore, it is the first object of the present invention to providethe compound of general formula (I):

whereinX represents an oxygen or sulfur atom;A represents a linear alkyl group of C2-4 which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 is a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;R3 represents a hydrogen or a halogen atom;R4 is a C1-6 alkyl group;n is 0 or 1.

It is also an object of the present invention the compound of generalformula (II):

whereinX represents an oxygen or sulfur atom;A represents a linear alkyl group of C2-4 which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 is a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;n is 0 or 1;p is 1 or 2.

A further object of the present invention is a process of obtaining thecompound of general formula (I), comprising the following steps:

(a) reacting of a compound of formula (III)

with a carboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula (V)

Wherein R1, R2 and R4 are as described for the compound of generalformula (I) and X1 is a halogen selected from the group comprisingchlorine and bromine, to obtain a compound of formula (VI)

(b) reacting the compound (VI) obtained in step (a) with a reducingagent to obtain the compound of formula (VII)

(c) reacting the compound (VII) obtained in step (b) with atetraalkylorthocarbonate selected from the group comprising thetetramethylorthocarbonate and tetraethyl orthocarbonate, to obtain thecompound of formula (Ia)

wherein R3 represents a hydrogen atom and “n” represents zero or one.

In addition to the aforementioned step, the process for obtaining thecompound of general formula (I) can further comprise the step of:

(d) reacting the compound of formula (Ia) obtained in step (c) with ahalogenating agent selected from the group comprisingN-bromosuccinimide, N-chlorosuccinimide and N-iodosuccinimide, to obtainthe compound of formula (Ia), wherein R3 represents a halogen selectedfrom the group comprising bromine, chlorine and iodine.

In another embodiment, the process of obtaining the compound of generalformula (I) of the present invention comprises the steps of:

(a) reacting the compound of formula (III)

with a carboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula (V)

wherein R1, R2 and R4 are as described for the compound of formula (I)and X1 represents a halogen selected from the group comprising chlorineand bromine, to obtain a compound of formula (VI)

(b) reacting the compound (VI) obtained in step (a) with a reducingagent to obtain the compound of formula (VII)

(e) reacting the compound (VII) obtained in step (b) with thiourea inorder to obtain the compound (VIII)

wherein R3 represents a hydrogen atom;(f) reacting the compound (VIII) obtained in step (e) with an alkylatingagent to obtain the compound of formula (Ib)

wherein R3 represents a hydrogen atom and “n” represents zero or one;(g) reacting the compound of formula (Ib) obtained in step (f) with ahalogenating agent selected from the group comprisingN-bromosuccinimide, N-chlorosuccinimide and N-iodosuccinimide, to obtainthe compound of general formula (Ib) wherein R3 represents a halogenselected from the group comprising bromine, chlorine and iodine.

Another object of the present invention is the process for obtaining thecompound of general formula (II) comprising the following steps:

(a) reacting the compound of formula (IX)

with a tetraalkylorthocarbonate selected from the group comprisingtetramethylorthocarbonate and tetraethyl orthocarbonate, to give acompound of formula (X)

wherein R2, “n” and “p” are as described for the compound of formula (I)or (II);(b) reacting the compound of formula (X) obtained in step (a) with adeprotecting agent to obtain a compound of formula (XI)

(c) reacting of the compound of formula (XI) obtained in (b) with acarboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula (V)

to obtain the compound of formula (IIa),

wherein R1 is as described for the compound of formula (II) and X1represents a bromine or chlorine atom;(d) reacting the compound of formula (IX)

with thiourea, obtaining the compound of formula (XII)

(e) reacting the compound of formula (XII) obtained in step (d) with analkylating agent to obtain the compound of formula (XIII)

wherein “n” is as described for the compound of formulae (I) or (II);(f) reacting the compound obtained in (e) with a deprotecting agent toobtain a compound of formula XIV:

(g) reacting the compound of formula (XIV) obtained in (f) with acarboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula (V)

to obtain the compound of formula (IIb):

A further object of the present invention is a pharmaceuticalcomposition characterized for comprising a compound of general formula(I):

a)

whereinX represents an oxygen or sulfur atom;A represents a linear alkyl group of C2-4 which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 represents a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;R3 represents a hydrogen or a halogen atom;R4 represents a C1-6 alkyl group;n is 0 or 1; andb) at least one pharmaceutically acceptable vehicle.

A further object of the present invention is a pharmaceuticalcomposition characterized for comprising a compound of general formula(II):

(a)

whereinX represents an oxygen or sulfur atom;A represents a linear C2-4 alkyl group which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 is a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;n is 0 or 1;p is 1 or 2; andb) at least one pharmaceutically acceptable vehicle.

In addition, a further object of the present invention is the use of thecompound of general formula (I):

whereinX represents an oxygen or sulfur atom;A represents a linear alkyl group of C2-4 which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 represents a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;R3 represents a hydrogen or halogen atom;R4 represents a C1-6 alkyl group,n is 0 or 1;in the manufacture of a drug for the treatment of psychiatric disordersand/or sleep disorders.

In addition, a further object of the present invention is the use of thecompound of general formula (II):

whereinX represents an oxygen or sulfur atom;A represents a linear alkyl group of C 2-4 which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 represents a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;n is 0 or 1;p is 1 or 2,in the manufacture of a drug for the treatment of psychiatric disordersand/or sleep disorders.

Another object of the present invention is a method of treatingpsychiatric disorders and/or sleep disorders, which comprises inadministering to a mammal a therapeutically effective amount of thecompound of general formula(I):

whereinX represents an oxygen or sulfur atom;A represents a linear alkyl group of C2-4 which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 represents a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;R3 represents a hydrogen or a halogen atom;R4 represents a C1-6 alkyl group,n is 0 or 1.

Another object of the present invention is a method of treatingpsychiatric disorders and/or sleep disorders, which comprisesadministering to a mammal a therapeutically effective amount of thecompound of general formula (II):

whereinX represents an oxygen or sulfur atom;A represents a linear alkyl group of C 2-4 which may have one or morehydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 represents a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;n is 0 or 1;p is 1 or 2.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1. Calculation of pKa values for benzimidazole (A) and itsderivative substituted with a methoxy group at the 2-position of ring(B).

FIG. 2. Example of the process for obtaining the compound of generalformula (I), including compounds of formulae (Ia) and (Ib).

FIG. 3. Example of the process for obtaining the compound of the generalformula (II), including compounds of formulae (IIa) and (IIb).

DETAILED DESCRIPTION OF THE INVENTION

The reduced melatonergic activity of benzimidazole analogs previouslyreported in the literature has been improved in the compounds of thepresent invention.

This improvement could be explained by the addition of electronwithdrawing substituents at the 2-position of the ring, which increasesthe population of molecules in a non-ionized form and mimics theneutrality of the indole present in the melatonin molecule, a naturalagonist of melatonergic receptors.

Affinity differences between indolic and benzimidazole derivatives couldbe explained by analyzing the stability of the conjugated acids of thebenzimidazole system, i.e., by analyzing pKa values and the populationsof molecules that are neutral or protonated (positive charge) at pH=7.This is because, in the case of melatonin, a melatonergic agonist withhigh affinity for MT1 and MT2 receptors, it would be expected that 100%of the population of molecules in solution would be in the neutral formsince it is a non-ionizablemolecule at pH=7. In addition, by analyzingthe ring structures of other potent agonists of melatonergic receptorsMT1 and MT2, such as Ramelteon, one can also observe the majority of theneutral form in these structures. Thus, for benzimidazole derivatives,lower pKa values could better mimic the observed neutrality formelatonin, and consequently have higher affinity for MT1 and MT2receptors.

If an unsubstituted benzimidazole derivative is protonated (generatingits conjugate acid), the entire system delocalizes the electron densitythrough the pi orbitals in order to stabilize the positive charge in thering. In the case of unsubstituted benzimidazole, this results in a pKavalue slightly above 6 (J. Org. Chem., 1961, 26 (8), pp 2789-2791). Inother words, a significant population of protonated species withpositive formal charge exists at pH=7. However, if the benzimidazolederivative is substituted at the 2-position of the ring with an electronwithdrawing group, the substituted derivative would have an electronwithdrawal caused by inductive effect in the benzimidazole ring, thuscausing a greater destabilization of the protonated form and a greaterpopulation of molecules in the neutral form. This factor would lower thepKa value of the benzimidazole derivatives substituted with an electronwithdrawing group. Indeed, calculation of the pKa values for theconjugated acids of the benzimidazole ring and its derivativesubstituted with a methoxy at the 2-position of the ring demonstrated alower pKa for the latter. The values were obtained using the programsEpik (J. Comput. Aided Mol. Des., 2010, 24, 591-604) and Jaguar (Int. J.Quantum Chem., 2013, 113 (18), 2110-2142), as shown in FIG. 1.

Based on this new and inventive premise of substitution of thebenzimidazole nucleus at position 2 to obtain a more acidic molecule forthe protonated species, a surprising result of a greater affinity formelatonergic receptors was achieved. A binding of 66% (in MT1) and 52%(in MT2) was observed with the unsubstituted benzimidazole derivative(IA2-116) and 100% (in MT1) and 98% (in MT2) with the2-methoxy-substituted benzimidazole derivative (IA2-118) (both at theconcentration of 1 uM). The binding improvement can be explained since,at neutral pH, there is a larger population of IA2-118 in the neutralform, as well as melatonin.

The benzimidazole compounds of the present invention are represented bythe general formula (I)

whereinX is an oxygen or sulfur atom;A represents a linear C2-4 alkyl group which may have one or more of itshydrogens substituted by an alkyl group selected from methyl, ethyl,propyl or isopropyl;R1 represents a C1-6 alkyl group, or C2-6 alkenyl, or C2-6 alkynyl, orC1-6 haloalkyl, or C3-6 cycloalkyl, or C1-2 alkyl-C3-6 cycloalkyl;R2 represents a hydrogen or a C1-3 alkyl group;R3 represents a hydrogen or a halogen atom;R4 represents a C1-6 alkyl group,n is 0 or 1and by its particular realization where the substituent —O—R4 forms athird cycle through the substitution of a vicinal hydrogen in thebenzene ring, which is represented by the general formula (II)

wherein X, R 1, R 2 and “n” are as described for the compound of generalformula (I) and “p” represents 1 or 2.

In order to clarify or elucidate the terms used in the present inventionand their scope, more detailed definitions of the concepts presented inthis document are shown.

In the present invention, unless otherwise defined, the terms alkyl,haloalkyl, cycloalkyl, alkenyl and alkynyl include both branched andunbranched derivatives.

The term alkyl refers to a straight or branched chain hydrocarbon whichis fully saturated. Non-limiting examples of alkyls are: methyl, ethyl,propyl, butyl, pentyl, hexyl and isomers thereof.

The terms alkenyl and alkynyl correspond to straight or branched chainhydrocarbons containing unsaturation, alkenyls having at least onedouble bond and the alkynyls having at least one triple bond.Non-limiting examples of alkenyls and alkynyls are: ethenyl, propenyl,butenyl, pentenyl, hexenyl, ethynyl, propynyl, butynyl, pentynyl,hexynyl and isomers thereof.

The term haloalkyl corresponds to an alkyl group containing at least oneof its hydrogens substituted by a halogen selected from the groupcomprising fluorine, chlorine, bromine and iodine. Non-limiting examplesof haloalkyls are: chloromethyl, chloroethyl, chloropropyl, chlorobutyl,bromomethyl, bromoethyl, bromopropyl, bromobutyl, fluorobutyl,fluoroethyl, fluoropropyl, fluorobutyl, trichloromethyl,trifluoromethyl, tribromomethyl, iodomethyl, iodoethyl, iodopropyl andisomers thereof.

The term cycloalkyl corresponds to fully saturated monocyclichydrocarbons. Non-limiting examples are cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term alkyl-cycloalkyl corresponds to a C3-6 cycloalkyl which isattached to a compound by an alkyl group comprising at least one carbonatom.

The halogens preferably selected for use in the present inventioncorrespond to fluorine, bromine, chlorine and iodine.

All definitions of compounds described herein, in addition to possiblevariations in their chemical forms, also include their structural andphysical modifications, including possible isomers, their polymorphicforms, solvates and hydrates or amorphous form.

In specific cases where the compound of the present invention hasasymmetric carbons, pure enantiomers, racemic mixtures thereof andpossible diastereomers are included within the scope of the presentinvention.

In the event that the compound of the present invention shows cis-transgeometric isomerism or E-Z isomerism, it is understood that theseindependent or associated isomers are within the scope of thisinvention.

The preferred, but not limited, examples of the compound of generalformula (I) include:

-   -   N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl) acetamide;    -   N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)propionamide;    -   N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)butyramide;    -   N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclopropane        carboxamide;    -   N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclobutanecarboxamide;    -   N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclopentane        carboxamide;    -   N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclohexane        carboxamide;    -   N-(3-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)propyl) acetamide;    -   N-(3-(2,6-dimethoxy-1H-benzimidazol-1-yl)propyl)acetamide;    -   N-(2-(2,6-dimethoxy-1H-benzimidazol-1-yl)ethyl) acetamide;    -   N-(2-(2,6-dimethoxy-1H-benzimidazol-1-yl)ethyl)propionamide;    -   N-(2-(2,6-dimethoxy-1H-benzimidazol-1-yl)ethyl)butyramide;    -   N-(1-(2-Ethoxy-6-methoxy-1H-benzimidazol-1-yl)propan-2-yl)        acetamide;    -   2-Bromo-N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)        acetamide;    -   N-(2-(6-methoxy-2-(methylthio)-1H-benzimidazol-1-yl)ethyl)        acetamide;    -   N-(2-(5-bromo-2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)        acetamide;    -   N-(2-(5-chloro-2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)        acetamide;    -   N-(3-(5-chloro-2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)propyl)        acetamide;    -   N-(3-(5-chloro-2,6-dimethoxy-1H-benzimidazol-1-yl)propyl)        acetamide;    -   N-(2-(5-chloro-2,6-dimethoxy-1H-benzimidazol-1-yl)ethyl)        acetamide;    -   N-(2-(5-chloro-2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclopropane        carboxamide;    -   N-(2-(7-chloro-2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)        acetamide

The preferred, but not limited, examples of the compound of generalformula (II) include:

-   -   N-(2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)        acetamide;    -   N-(2-(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)        acetamide.

The compounds of general formulae (I) and (II) of the present inventionhave been synthesized according to FIGS. 2 and 3 shown in the presentinvention.

According to FIG. 2, the starting compound (III), obtained from asimilar procedure to that described by Depreux (Synthetic Communications1994, 24 (15), 2123-2132), is acylated using anhydrides or carboxylicacids halides for the introduction of the R1 substituent, resulting inthe intermediate compound (VI). Then, the compound (VI) is reduced tothe intermediate (VII). The intermediate (VII) is cyclized usingtetraalkyl orthocarbonates, such as tetramethylorthocarbonate andtetraethyl orthocarbonate, resulting in the compound of formula (Ia),wherein the substituent R3 corresponds to a hydrogen. The introductionof the halogen as substituent R3 is performed in a subsequent step, byreacting the compound (Ia) with an N-halosuccinimide selected from thegroup comprising N-bromosuccinimide, N-chlorosuccinimide andN-iodosuccinimide, resulting in the compound of formula (Ia) wherein R3is bromide, chlorine or iodine.

Alternatively, the cyclization of intermediate (VII) with thiourearesults in the formation of intermediate (VIII), which is alkylatedusing an alkylating agent for the formation of the compound of formula(Ib) where R3 corresponds to a hydrogen. Similarly, the introduction ofthe halogen as substituent R3 is performed in a subsequent step byreacting the compound (Ib) with an N-halosuccinimide selected from thegroup comprising N-bromosuccinimide, N-chlorosuccinimide andN-iodosuccinimide, resulting in the compound of formula (Ib) wherein R3is bromide, chlorine or iodine.

FIG. 3 describes the obtainment of the compound of general formula (II).According to this diagram, the intermediate (IX), obtained from asimilar procedure to that described by Koike et al. (Journal ofMedicinal Chemistry 2011, 54 (12), 4207-4218), is cyclized usingtetraalkylorthocarbonates, such as tetramethylorthocarbonate andtetraethyl orthocarbonate, resulting in the intermediate (X). Thisintermediate is deprotected to result in the intermediate (XI), which isacylated using carboxylic acid anhydrides or halides for theintroduction of the R1 substituent, thereby obtaining the compound offormula (IIa).

Alternatively, cyclization of intermediate (IX) with thiourea results inthe formation of intermediate (XII), which is alkylated using analkylating agent resulting in the intermediate (XIII). Then, theintermediate (XIII) is deprotected and acylated with carboxylic acidanhydrides or halides for the introduction of the R1 substituent,thereby obtaining the compound of formula(IIb).

It is noteworthy that compounds of formulae (Ia) and (Ib) are integralpart of the invention and are included in the compound of generalformula (I).

Similarly, the compounds of formulae (IIa) and (IIb) are an integralpart of the invention and are included in the compound of generalformula (II).

Therefore, a further object of the present invention is the process toobtain the compound of general formula (I), comprising the followingsteps:

(a) reacting of a compound of formula(III)

with a carboxylic acid anhydride of formula(IV)

or with a carboxylic acid halide of formula(V)

wherein R1, R2 and R4 are as described for the compound of generalformula (I) and X1 corresponds to a halogen selected from the groupcomprising chlorine and bromine, to obtain a compound of formula (VI)

(b) reacting of the compound (VI) obtained in step (a) with a reducingagent to obtain the compound of formula (VII)

(c) reacting of the compound (VII) obtained in step (b) with atetraalkylorthocarbonate selected from the group comprisingtetramethylorthocarbonate and tetraethyl orthocarbonate, to obtain thecompound of formula(Ia)

wherein R3 represents a hydrogen atom and “n” represents zero or one;reacting of the compound of formula (Ia) obtained in step (c) with ahalogenating agent selected from the group comprisingN-bromosuccinimide, N-chlorosuccinimide and N-iodosuccinimide, to obtainthe compound of formula (Ia), wherein R3 represents a halogen selectedfrom the group comprising bromine, chlorine and iodine;

Therefore, a further object of the present invention is the process toobtain the compound of general formula(I), comprising the followingsteps:

(a) reacting of a compound of general formula (III)

with a carboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula(V)

wherein R1, R2 and R4 are as described for the compound of formula (I)and X1 represents a halogen selected from the group comprising chlorineand bromine, to obtain a compound of formula(VI)

(b) reacting of the compound (VI) obtained in step (a) with a reducingagent to obtain the compound of formula(VII)

(e) reacting of the compound (VII) obtained in step (b) with thiourea inorder to obtain the compound (VIII)

wherein R3 represents a hydrogen atom;(f) reacting the compound (VIII) obtained in step (e) with an alkylatingagent to obtain the compound of formula (Ib)

wherein R3 represents a hydrogen atom and “n” corresponds to zero orone;(g) reacting the compound of formula (Ib) obtained in step (f) with ahalogenating agent selected from the group comprisingN-bromosuccinimide, N-chlorosuccinimide and N-iodosuccinimide, to obtainthe compound of general formula (Ib) wherein R3 represents a halogenselected from the group comprising bromine, chlorine and iodine.

Another object of the present invention is the process to obtain thecompound of general formula (II) comprising the following steps:

(a) reacting of a compound of formula(IX):

with a tetraalkylorthocarbonate selected from the group comprisingtetramethylorthocarbonate and tetraethyl orthocarbonate, to obtain acompound of formula (X)

wherein R2, “n” and “p” are as described for the compound of generalformula (II);(b) reacting the compound of formula (X) obtained in step (a) with adeprotecting agent to obtain a compound of formula (XI):

(c) reacting of the compound of formula (XI) obtained in (b) with acarboxylic acid anhydride of formula(IV):

or with a carboxylic acid halide of formula(V):

to obtain the compound of formula(IIa),

wherein R1 is as described for the compound of formula (I) and X1represents a bromine or chlorine atom.

In an optional embodiment, the process of obtaining the compound ofgeneral formula (II) comprises the following steps: (d) reacting of acompound of formula (IX)

with thiourea resulting in the compound of formula(XII)

(e) reacting the compound of formula (XII) obtained in step (d) with analkylating agent resulting in the compound of formula (XIII)

wherein “n” is as described for the compound of formula (I); (f)reacting the compound obtained in (e) with a deprotecting agent toobtain a compound of formula XIV:

(g) reacting the compound of formula (XIV) obtained in (f) with acarboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula(V)

to obtain the compound of formula(IIb):

Once again, it is noteworthy that the compounds of formulae (Ia) and(Ib) are an integral part of the invention and are included in thecompound of general formula (I). Similarly, the compounds of formulae(IIa) and (IIb) are an integral part of the invention and are includedin the compound of formula (II).

The carboxylic acid anhydrides used in the process of obtaining thecompound of formulae (I) or (II) comprise commercially availablecompounds or those synthetically produced. Non-limiting examples ofcarboxylic acid anhydrides which may be used in this invention includeacetic, propionic, butyric, crotonic, valeric anhydrides, among others.

The carboxylic acid halides employed in the process of obtaining thecompound of formula (I) or (II), comprise both the commerciallyavailable and the synthetically prepared compounds. Non-limitingexamples of carboxylic acid halides include the chlorides and bromidesof acetic, propanoic, butanoic, valeric, cyclopropanecarboxylic,cyclobutanecarboxylic, cyclopentanecarboxylic, cyclohexanecarboxylic,alpha-bromoacetic, alpha-chloroacetic acids, among others.

Alkylating agents are substances that transfer alkyl groups betweenmolecules. There are several alkylating agents available in the market,as well as a variety of reactions used for this purpose. Non-limitingexamples of alkylating agents used in the process described in thisinvention correspond to alkyl halides, such as methyl and ethyl bromidesor iodides.

Deprotection agents are chemicals used to remove protecting groups.Protecting groups, in turn, are chemical groups used to protect specificfunctions which, when unmodified, are likely to react or undergoalteration with reagents used for structural modifications directed toother positions of the molecule. In the present invention a non-limitingexample of deprotection agent capable of removing thetert-butoxycarbonyl protecting group from the intermediates (X) and(XIII) corresponds to trifluoroacetic acid.

In the present invention, a reducing agent has the role of promoting thetransformation of an aromatic nitro group into an amino group. Severalreagents may be used to promote this reduction. Non-limiting examples oftypical reducing agents of aromatic nitro groups include iron or tin inhydrochloric acid medium, zinc, several metal catalysts, among others.

It is noteworthy that the present invention also comprises isomers,tautomers, pure enantiomers, racemic mixtures and diastereomers of thecompound of general formulae (I) or (II), as well as mixtures thereof atany ratios.

Depending on the medium used for crystallization, the compound offormulae (I) or (II) may show different aspects. Thus, the presentinvention also comprises the amorphous form, the solvates, hydrates andpolymorphs of the compound of formulae (I) or (II).

In order to exert its activity, the compound of formulae (I) or (II)should be administered to an animal, mammal, particularly a human,preferably as a pharmaceutical composition, i.e., associated opharmaceutically acceptable vehicles which are acceptable to each routeof administration.

The pharmaceutical compositions of the present invention contain one ormore compounds herein proposed, as active ingredient, associated withone or more pharmaceutically acceptable vehicles. The active ingredientis commonly mixed, diluted or encapsulated with at least one vehicle.The final composition may be a capsule, sachet, paper or other way ofcontainment. When the vehicle is a diluent, it may be in solid,semi-solid, or liquid form, acting as a carrier, excipient or medium forthe active ingredient. Thus, the composition may be tablets, pills,powders, sachets, suspensions, emulsions, solutions, aerosols (in solidor liquid medium), creams, hard or soft capsules, suppositories,injections.

In the present invention, it is considered a pharmaceutically acceptablevehicle any substance other than the compound of general formulae (I) or(II), which has been intentionally added thereto to produce apharmaceutical dosage form suitable to a route of administration.Non-limiting examples of pharmaceutical acceptable vehicle (excipients)suitable for pharmaceutical compositions are described in Handbook ofPharmaceutical Manufacturing Formulations-Vol. 1 to 6-2004-Sarfaraz K.Niazi-CRCPress and Remington's Pharmaceutical Sciences, Mack Publishing.

Non-limiting examples of routes of administration of the compositioncomprising the compound of general formulae (I) or (II) are oral,parenteral, nasal, rectal, transmucosal and transdermal routes, oraladministration being particularly preferred.

The therapeutic dose to be used with respect to the compounds of thepresent invention should be planned and calculated according to route ofadministration chosen, age, weight and condition of the patient anddisorder severity. Overall, the compounds of the present invention areadministered in therapeutically effective doses ranging from about 0.1mg to about 2,000 mg per day. Effective doses may be extrapolated fromdose-response curves obtained from in vitro or animal models. Typically,the physician will administer the compound to a suitable dose in orderto achieve the expected effect.

The examples described in the experimental section are intended toexemplify one of the several ways of carrying out the invention, butwithout limiting the scope thereof.

Example 1

N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)acetamide

(A) N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)acetamide

In a 500 ml reactor equipped with reflux condenser, magnetic stirringand heating, N¹-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine (6.0 g, 28.4mmol) (Depreux Et al., Synthetic Communications 1994, col. 24 (15), pp.2123-2132), ethanol (200 ml) and acetic anhydride (2.78 ml, 29.2 mmol)were added. The reaction medium was heated to a temperature of 60° C.and kept under stirring for 1 hour to complete the reaction. The ethanolwas roto-evaporated to dryness and the residue dissolved in chloroform(400 ml). The chloroform solution was washed with 15% aqueous sodiumcarbonate solution (2×200 ml). The organic phase was separated, driedwith magnesium sulfate and roto-evaporated to yield the title compoundas a yellow solid which was used directly in the next step. (m=6.8 g.Yield: 94.5%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl)acetamide

In a 500 ml reactor,N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)acetamide (3.0 g, 11.8 mmol)and methanol (300 ml) were added. The mixture was heated to atemperature of approximately 45° C. under stirring to dissolve thesolid. Then the solution was cooled to room temperature and zinc powder(11.55 g, 176 mmol) and ammonium formate (5.61 g, 89.0 mmol) were addedunder vigorous stirring. The mixture was kept under stirring forapproximately 1 hour and then gravity filtered. The filtrate wasroto-evaporated and the residue was extracted with dichloromethane(3×300 ml). The combined organics were washed with 6M aqueous sodiumhydroxide solution (2×500 ml), followed by saturated sodium chloridesolution (400 ml). The organic phase was separated, dried with magnesiumsulfate and roto-evaporated yielding oil, which was used directly in thenext step. (m=2.4 g. Yield: 91%)

(C) N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl) acetamide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)acetamide (500 mg, 2.24mmol), were added tetraethyl orthocarbonate (1.72 g, 8.96 mmol) andsubsequently acetic acid (0.013 g, 0.216 mmol). The reaction was heatedto 80° C. and kept at this temperature for 30 min. Then the reactionmedium was allowed to return to room temperature and ethyl ether (25 ml)was added. The precipitated solid was filtered, washed with ethyl ether(25 ml) and purified by MPLC (CHC13:MeOH 9:1) resulting in a white solidproduct. (m=385 mg. Yield: 62%)

¹H NMR (300 MHz, CHLOROFORM-d) δppm 1.45 (t, J=7.08 Hz, 4H) 1.92 (s, 3H)3.58 (q, J=5.89 Hz, 3H) 3.83 (s, 3H) 4.06-4.15 (m, 3H) 4.51 (q, J=7.08Hz, 2H) 5.77 (br s, 1H) 6.72 (s, 1H) 6.75-6.80 (m, 1H) 7.40 (d, J=8.57Hz, 1H);

¹³C NMR (75 MHz, CHLOROFORM-d) δppm 14.71 (s, 1 C) 23.10 (s, 1 C) 38.99(s, 1 C) 41.23 (s, 1 C) 56.01 (s, 1 C) 66.12 (s, 1 C) 93.51 (s, 1 C)109.24 (s, 1 C) 118.07 (s, 1 C) 134.05 (s, 1 C) 134.35 (s, 1 C) 155.55(s, 1 C) 156.78 (s, 1 C) 170.53 (s, 1 C).

Example 2

N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)propionamide

(A) N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)propionamide

In a 100 ml reactor with magnetic stirring,N1-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine(1 g, 4.73 mmol),dichloromethane (50 ml) and triethylamine (0.67 ml, 4.81 mmol) wereadded. The reaction medium was kept under stirring and a solution ofpropionyl chloride (0.42 ml, 4.80 mmol) in dichloromethane (10 ml) wasslowly added through an addition funnel. The reaction medium was keptunder stirring at room temperature for 2 hours. After the completion ofthe reaction, 20 ml of 10% aqueous hydrochloric acid solution (20 ml)were added. The dichloromethane was separated and the aqueous phaseextracted with dichloromethane (2×20 ml). The organic phase was washedwith 5% aqueous bicarbonate solution (100 ml) and saturated sodiumchloride solution (100 ml). The organic extract was separated, driedwith anhydrous magnesium sulfate and roto-evaporated, yielding a yellowsolid product which was used directly in the next step. (m=1.14 g.Yield: 90%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl) propionamide

N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)propionamide (0.56 g, 2.10mmol) and methanol (50 ml) were added to a 100 ml reactor. The mixturewas heated to a temperature of approximately 45° C. under stirring todissolve the solid. Then the solution was cooled to room temperature andzinc powder (2.04 g, 31.2 mmol) and ammonium formate (0.99 g, 15.7 mmol)were added under vigorous stirring. The mixture was kept under stirringfor approximately 1 hour and then gravity filtered. The filtrate wasroto-evaporated and dichloromethane (300 ml) was added to the residue.The mixture was kept under stirring to extract the product, filtered,washed with 6M aqueous sodium hydroxide solution (2×200 ml), followed bysaturated sodium chloride solution (300 ml). The organic phase wasseparated, dried with magnesium sulfate and roto-evaporated to drynessyielding oil, which was used directly in the next synthetic step.(m=0.45 g. Yield: 90%)

(C) N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl) propionamide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)propionamide (450 mg, 1.90mmol), tetraethyl orthocarbonate (1.46 g, 7.59 mmol) and subsequentlyacetic acid (0.011 g, 0.189 mmol) were added. The reaction was heated to80° C. and kept at this temperature for 30 min. Then the reaction mediumwas allowed to return to room temperature and ethyl ether (25 ml) wasadded. The precipitated solid was filtered, washed with ethyl ether (25ml) and purified by MPLC (CHC13:MeOH 9:1) resulting in a white solidproduct. (m=309 mg. Yield: 56%) ¹H NMR (500 MHz, CHLOROFORM-d) δppm1.18-1.35 (m, 4H) 1.46 (t, J=7.10 Hz, 2H) 2.13 (q, J=7.55 Hz, 1H) 3.59(q, J=5.89 Hz, 1H) 3.77-3.84 (m, 2H) 4.11 (t, J=5.76 Hz, 1H) 4.55 (q,J=7.15 Hz, 1H) 5.64 (br s, 1H) 6.77 (dd, J=8.64, 2.48 Hz, 1H) 7.26 (s,1H) 7.40 (d, J=8.64 Hz, 1H)

Example 3

N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)butyramide

(A) N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)butyramide

In a 100 ml reactor with magnetic stirring,N1-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine (1 g, 4.73 mmol),dichloromethane (50 ml) and triethylamine (0.67 ml, 4.80 mmol) wereadded. The reaction medium was kept under stirring and a solution ofbutanoyl chloride (0.49 ml, 4.73 mmol) in dichloromethane (10 ml) wasslowly added through an addition funnel. The reaction medium was keptunder stirring at room temperature for 2 hours. After the completion ofthe reaction, 10% aqueous hydrochloric acid solution (10 ml) was added.The dichloromethane was separated and the aqueous phase extracted withdichloromethane (2×20 ml). The organic phase was washed with 5% aqueousbicarbonate solution (100 ml) and saturated sodium chloride solution(100 ml). The organic extract was separated, dried with anhydrousmagnesium sulfate and roto-evaporated, yielding a yellow solid productwhich was used directly in the next step. (m=1.17 g. Yield: 88%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl)butyramide

N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl) butyramide (0.51 g, 1.81mmol) and methanol (50 ml) were added to a 100 ml reactor. The mixturewas heated to a temperature of approximately 45° C. under stirring todissolve the solid. Then the solution was cooled to room temperature andpowdered zinc (1.76 g, 26.9 mmol) and ammonium formate (0.86 g, 13.6mmol) were added under vigorous stirring. The mixture was kept understirring for approximately 1 hour and then gravity filtered. Thefiltrate was roto-evaporated, the residue extracted with dichloromethane(300 ml), washed with 6M aqueous sodium hydroxide solution (2×200 ml),followed by saturated aqueous sodium chloride solution (300 ml). Theorganic phase was separated, dried with magnesium sulfate androto-evaporated to dryness yielding oil, which was used directly in thenext step of synthesis. (m=0.40 g. Yield: 87.8%)

(C) N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl) butyramide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)butyramide (400 mg, 1.59mmol) tetraethyl orthocarbonate (1.22 g, 6.37 mmol) and subsequentlyacetic acid (0.010 g, 0.159 mmol) were added. The reaction was heated to80° C. and kept at this temperature for 30 min. Then the reaction mediumwas allowed to return to room temperature and ethyl ether (20 ml) wasadded. The precipitated solid was filtered, washed with ethyl ether (20ml) and purified by MPLC (CHC13:MeOH 9:1) resulting in a white solidproduct. (m=258 mg. Yield: 53%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 0.91 (t, J=7.38 Hz, 3H) 1.46 (t,J=7.08 Hz, 3H) 1.57-1.67 (m, 3H) 2.05-2.10 (m, 2H) 3.60 (q, J=5.97 Hz,2H) 3.81-3.86 (m, 3H) 4.08-4.14 (m, 2H) 4.54 (q, J=7.13 Hz, 2H) 5.64 (brs, 1H) 6.72 (s, 1H) 6.76-6.79 (m, 1H) 7.26 (s, 1H) 7.40 (d, J=8.61 Hz,1H)

Example 4

N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclopropanecarboxamide

(A) N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclopropanecarboxamide

In a 100 ml reactor with magnetic stirring, N1-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine (1 g, 4.73 mmol), dichloromethane (50 ml) andtriethylamine (0.67 ml, 4.80 mmol) were added. The reaction medium waskept under stirring and a solution of cyclopropanecarbonyl chloride(0.43 ml, 4.73 mmol) in dichloromethane (10 ml) was slowly added throughan addition funnel. The reaction medium was kept under stirring at roomtemperature for 2 hours. After the completion of the reaction, 10%aqueous hydrochloric acid solution (10 ml) was added. Thedichloromethane was separated and the aqueous phase extracted withdichloromethane (2×20 ml). The organic phase was washed with 5% aqueousbicarbonate solution (100 ml) and saturated sodium chloride solution(100 ml). The organic extract was separated, dried with anhydrousmagnesium sulfate and roto-evaporated, yielding a yellow solid productwhich was used directly in the next step. (m=1.17 g. Yield: 88.5%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl)cyclopropane carboxamide

In a 200 ml reactor,N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclopropane carboxamide(0.79 g, 2.83 mmol) and methanol (70 ml) were added. The mixture washeated to a temperature of approximately 45° C. under stirring todissolve the solid. Then the solution was cooled to room temperature andpowdered zinc (2.78 g, 42.5 mmol) and ammonium formate (1.34, 22.3 mmol)were added under vigorous stirring. The mixture was kept under stirringfor approximately 1 hour and then gravity filtered. The filtrate wasroto-evaporated and dichloromethane (300 ml) was added to the residue.The mixture was kept under stirring to extract the product, filtered,washed with 6M aqueous sodium hydroxide solution (2×150 ml), followed bysaturated sodium chloride solution (150 ml). The organic phase wasseparated, dried with magnesium sulfate and roto-evaporated to drynessyielding oil, which was used directly in the next step of synthesis.(m=0.64 g. Yield: 90.8%)

(C) N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl) cyclopropanecarboxamide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)cyclopropane carboxamide (500mg, 2.01 mmol), tetraethyl orthocarbonate (1.54 g, 8.01 mmol) andsubsequently acetic acid (0.012 g, 0.201 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (25 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (25 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin a white solid product. (m=350 mg. Yield: 57.5%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 0.67-0.77 (m, 2H) 0.80-1.03 (m, 2H)1.19-1.34 (m, 1H) 1.45 (t, J=7.10 Hz, 3H) 3.61 (q, J=5.95 Hz, 2H) 3.83(s, 3H) 4.10 (t, J=5.65 Hz, 2H) 4.51 (q, J=7.02 Hz, 2H) 5.96 (br s, 1H)6.71 (d, J=2.29 Hz, 1H) 6.78 (dd, J=8.70, 2.44 Hz, 1H) 7.40 (d, J=8.54Hz, 1H)

Example 5

N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclobutanecarboxamide

(A) N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclobutanecarboxamide

In a 100 ml reactor with magnetic stirring,N1-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine (1 g, 4.73 mmol),dichloromethane (50 ml) and triethylamine (0.67 ml, 4.80 mmol) wereadded. The reaction medium was kept under stirring and a solution ofcyclobutanecarbonyl chloride (0.54 ml, 4.73 mmol) in dichloromethane (10ml) was slowly added through an addition funnel. The reaction medium waskept under stirring at room temperature for 2 hours. After thecompletion of the reaction, 10% aqueous hydrochloric acid solution (10ml) was added. The dichloromethane was separated and the aqueous phasewas extracted with dichloromethane (2×20 ml). The organic phase waswashed with 5% aqueous bicarbonate solution (100 ml) and saturatedsodium chloride solution (100 ml). The organic extract was separated,dried with anhydrous magnesium sulfate and roto-evaporated, yielding ayellow solid product which was used directly in the next step. (m=1.25g. Yield: 90%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl)cyclobutanecarboxamide

In a 200 ml reactorN-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclobutanecarboxamide (0.785g, 2.68 mmol) and methanol (60 ml) were added. The mixture was heated toa temperature of approximately 45° C. under stirring to dissolve thesolid. Then the solution was cooled to room temperature and 2.60 g ofpowdered zinc (2.60 g, 39.8 mmol) and 1.26 g of ammonium formate (1.26g, 20.0 mmol) were added under vigorous stirring. The mixture was keptunder stirring for approximately 1 hour and then gravity filtered. Thefiltrate was roto-evaporated and dichloromethane (300 ml) was added tothe residue. The mixture was kept under stirring to extract the product,filtered, washed with 6M aqueous sodium hydroxide solution (2×150 ml),followed by saturated sodium chloride solution (150 ml). The organicphase was separated, dried with magnesium sulfate and roto-evaporated todryness yielding oil, which was used directly in the next step ofsynthesis. (m=0.64 g. Yield: 90.8%)

(C)N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclobutanecarboxamide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl) cyclobutanecarboxamide (600mg, 2.28 mmol), tetraethyl orthocarbonate (1.75 g, 9.11 mmol) andsubsequently acetic acid (0.014 g, 0.23 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (30 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (30 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin a white solid product. (m=362 mg. Yield: 50%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.47 (t, J=7.10 Hz, 3H) 1.77-1.97(m, 2H) 2.04-2.11 (m, 2H) 2.17-2.25 (m, 2H) 2.85-2.92 (m, 1H) 3.60 (q,J=5.95 Hz, 2H) 3.83 (s, 3H) 4.11 (t, J=5.80 Hz, 2H) 4.55 (q, J=7.17 Hz,2H) 5.54 (br s, 1H) 6.71 (d, J=2.29 Hz, 1H) 6.78 (dd, J=8.70, 2.44 Hz,1H) 7.41 (d, J=8.70 Hz, 1H)

Example 6

N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclopentanecarboxamide

(A) N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclopentane carboxamide

N1-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine (1 g, 4.73 mmol),dichloromethane (50 ml) and triethylamine (0.67 ml, 4.80 mmol) wereadded to a 100 ml reactor with magnetic stirring. The reaction mediumwas kept under stirring and a solution of cyclopentanecarbonyl chloride(0.585 ml, 4.73 mmol) in dichloromethane (10 ml) was slowly addedthrough an addition funnel. The reaction medium was kept under stirringat room temperature for 2 hours. After the completion of the reaction,10% aqueous hydrochloric acid solution (10 ml) was added. Thedichloromethane was separated and the aqueous phase extracted withdichloromethane (2×20 ml). The organic phase was washed with 5% aqueousbicarbonate solution (100 ml) and saturated sodium chloride solution(100 ml). The organic extract was separated, dried with anhydrousmagnesium sulfate and roto-evaporated, yielding a yellow solid productwhich was used directly in the next step. (m=1.2 g. Yield: 83%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl) cyclopentane carboxamide

In a 50 ml reactorN-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclopentane carboxamide(0.100 g, 0.325 mmol) and methanol (20 ml) were added. The mixture washeated to a temperature of approximately 45° C. under stirring todissolve the solid. Then the solution was cooled to room temperature andzinc powder (0.317 g, 4.85 mmol) and ammonium formate (0.153 g, 2.43mmol) were added under vigorous stirring. The mixture was kept understirring for approximately 1 hour and then gravity filtered. Thefiltrate was roto-evaporated and dichloromethane (100 ml) was added tothe residue. The mixture was kept under stirring to extract the product,filtered, washed with 6M aqueous sodium hydroxide solution (2×50 ml),followed by saturated sodium chloride solution (50 ml). The organicphase was separated, dried with magnesium sulfate and roto-evaporated todryness yielding oil, which was used directly in the next step ofsynthesis. (m=0.082 g. Yield: 90.8%)

(C) N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclopentanecarboxamide

In a 10 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)cyclopentane carboxamide (82mg, 0.296 mmol), tetraethyl orthocarbonate (0.227 g, 1.18 mmol) andsubsequently acetic acid (0.0018 g, 0.030 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (5 ml) was added. The precipitated solid was filtered, washed withethyl ether (5 ml) and purified by MPLC (CHC13:MeOH 9:1) resulting in awhite solid product. (m=49 mg. Yield: 50%).

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.41-1.60 (m, 6H) 1.63-1.83 (m, 9H)2.35-2.44 (m, 1H) 3.60 (q, J=5.85 Hz, 2H) 3.82 (s, 3H) 4.10 (t, J=5.80Hz, 2H) 4.54 (q, J=7.17 Hz, 2H) 5.62 (br s, 1H) 6.71 (d, J=2.29 Hz, 1H)6.77 (dd, J=8.54, 2.44 Hz, 1H) 7.40 (d, J=8.70 Hz, 1H)

Example 7

N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclohexanecarboxamide

(A) N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclohexane carboxamide

N1-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine (1 g, 4.73 mmol),dichloromethane (50 ml) and triethylamine (0.67 ml, 4.80 mmol) wereadded to a 100 ml reactor with magnetic stirring. The reaction mediumwas kept under stirring and a solution of 0.64 ml of cyclohexanecarbonylchloride (0.64 ml, 4.73 mmol) in dichloromethane (10 ml) was slowlyadded through an addition funnel. The reaction medium was kept understirring at room temperature for 2 hours. After the completion of thereaction, 10% aqueous hydrochloric acid solution (10 ml) was added. Thedichloromethane was separated and the aqueous phase extracted withdichloromethane (2×20 ml). The organic phase was washed with 5% aqueousbicarbonate solution (100 ml) and saturated sodium chloride solution(100 ml). The organic extract was separated, dried with anhydrousmagnesium sulfate and roto-evaporated, yielding a yellow solid productwhich was used directly in the next step. (m=1.3 g. Yield: 86%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl)cyclohexane carboxamide

In a 50 ml reactor, 0.100 g ofN-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)cyclohexane carboxamide(0.100 g, 0.311 mmol) and methanol (20 ml) were added. The mixture washeated to a temperature of approximately 45° C. under stirring todissolve the solid. Then the solution was cooled to room temperature andpowdered zinc (0.030 g, 4.65 mmol) and ammonium formate (0.147 g, 2.33mmol) were added under vigorous stirring. The mixture was kept understirring for approximately 1 hour and then gravity filtered. Thefiltrate was roto-evaporated and dichloromethane (100 ml) was added tothe residue. The mixture was kept under stirring to extract the product,filtered, washed with 6M aqueous sodium hydroxide solution (2×50 ml),followed by saturated sodium chloride solution (50 ml). The organicphase was separated, dried with magnesium sulfate and roto-evaporated todryness yielding oil, which was employed directly in the next step ofsynthesis. (m=0.082 g. Yield: 90%)

(C) N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)cyclohexanecarboxamide

In a 10 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)cyclohexane carboxamide (82mg, 0.281 mmol), tetraethyl orthocarbonate (0.216 g, 0.113 mmol) andsubsequently acetic acid (0.0017 g, 0.028 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (5 ml) was added. The precipitated solid was filtered, washed withethyl ether (5 ml) and purified by MPLC (CHC13:MeOH 9:1) resulting in awhite solid product. (m=53.4 mg. Yield: 55%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.28-1.48 (m, 5H) 1.57-1.68 (m, 4H)1.69-1.79 (m, 4H) 1.97 (tt, J=11.73, 3.30 Hz, 1H) 3.60 (q, J=5.95 Hz,2H) 3.83 (s, 3H) 4.10 (t, J=5.72 Hz, 2H) 4.55 (q, J=7.17 Hz, 2H) 6.71(d, J=2.29 Hz, 1H) 6.77 (dd, J=8.70, 2.44 Hz, 1H) 7.41 (d, J=8.70 Hz,1H)

Example 8

N-(3-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)propyl) acetamide

(A) N-(3-((5-methoxy-2-nitrophenyl)amino)propyl) acetamide

In a 100 ml reactor, 3-chloro-4-nitroanisole (7.00 g, 37.3 mmol),1,3-propylene diamine (37 ml, 439 mmol) and cupric bromide (3.5 g, 15.7mmol) were added. The reaction medium was kept under stirring andheating at 60-65° C. for 4 hours. After cooling, the reaction medium wasdiluted with water (140 ml) and extracted with chloroform (3×220 ml).The organic phases were combined and washed with water (300 ml). Thechloroform was dried over magnesium sulfate and roto-evaporated todryness yielding oil, which was dissolved in ethanol (300 ml). To thissolution was added acetic anhydride (4.2 ml, 44.1 mmol), the reactionmedium was heated to 60° C. and kept under stirring for 1 hour. Then theethanol was roto-evaporated to dryness and the resulting oil dissolvedin ethyl acetate. This solution was washed with 15% aqueous sodiumcarbonate solution, the acetate phase separated, dried with anhydrousmagnesium sulfate and roto-evaporated to yield a yellow oil productwhich was used directly in the next step. (m=8.2 g. Yield: 82%)

(B) N-(3-((2-amino-5-methoxyphenyl)amino)propyl)acetamide

In a 200 ml reactor,N-(3-((5-methoxy-2-nitrophenyl)amino)propyl)acetamide (1.0 g, 3.74 mmol)and methanol (50 ml) were added. The mixture was kept under vigorousstirring and powdered zinc (3.65 g, 55.8 mmol) and ammonium formate(1.77 g, 28.1 mmol) were added. The mixture was kept under stirring forapproximately 1 hour and then gravity filtered. The filtrate wasroto-evaporated and dichloromethane (300 ml) was added to the residue.The mixture was kept under stirring to extract the product, filtered,dichloromethane was washed with 6M aqueous sodium hydroxide solution(2×150 ml), followed by saturated sodium chloride solution (150 ml). Theorganic phase was separated, dried with magnesium sulfate androto-evaporated to dryness yielding oil, which was used directly in thenext step of synthesis. (m=0.87 g. Yield: 98%)

(C) N-(3-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)propyl) acetamide

In a 50 ml reactor containingN-(3-((2-amino-5-methoxyphenyl)amino)propyl)acetamide (500 mg, 2.10mmol), tetraethyl orthocarbonate (1.62 g, 8.4 mmol) and subsequentlyacetic acid (0.013 g, 0.210 mmol) were added. The reaction was heated to80° C. and kept at this temperature for 30 min. Then the reaction mediumwas allowed to return to room temperature and ethyl ether (25 ml) wasadded. The precipitated solid was filtered and washed with ethyl ether(25 ml). The product was purified by MPLC (CHC13:MeOH 9:1) resulting ina white solid product. (m=356 mg. Yield: 58%)

¹H NMR (300 MHz, CHLOROFORM-d) δppm 1.49 (t, J=7.12 Hz, 3H) 1.93-2.09(m, 5H) 3.25 (q, J=6.68 Hz, 2H) 3.75-4.08 (m, 6H) 4.59 (q, J=7.09 Hz,2H) 5.59 (br s, 1H) 6.68 (d, J=2.26 Hz, 1H) 6.78 (dd, J=8.64, 2.44 Hz,1H) 7.42 (d, J=8.64 Hz, 1H); ¹³C NMR (75 MHz, CHLOROFORM-d) δppm 14.78(s, 1 C) 23.28 (s, 1 C) 28.56 (s, 1 C) 36.86 (s, 1 C) 39.50 (s, 1 C)56.05 (s, 1 C) 66.21 (s, 1 C) 93.90 (s, 1 C) 108.71 (s, 1 C) 118.11 (s,1 C) 133.86 (s, 1 C) 134.22 (s, 1 C) 155.37 (s, 1 C) 156.74 (s, 1 C)170.15 (s, 1 C).

Example 9

N-(3-(2,6-dimethoxy-1H-benzimidazol-1-yl) propyl) acetamide

In a 50 ml reactor containingN-(3-((2-amino-5-methoxyphenyl)amino)propyl) acetamide (Example 8 (B))(400 mg, 1.69 mmol), tetramethylorthocarbonate (92 g, 6.74 mmol) andsubsequently acetic acid (0.010 g, 0.169 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (25 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (25 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin a white solid product. (m=271 mg. Yield: 58%)

¹H NMR (300 MHz, CHLOROFORM-d) δppm 1.92-2.08 (m, 5H) 3.26 (q, J=6.72Hz, 2H) 3.75-3.86 (m, 3H) 3.93-4.20 (m, 6H) 5.57 (br s, 1H) 6.68 (d,J=2.32 Hz, 1H) 6.78 (dd, J=8.68, 2.44 Hz, 1H) 7.43 (d, J=8.62 Hz, 1H);

¹³C NMR (75 MHz, CHLOROFORM-d) δppm 23.26 (s, 1 C) 28.67 (s, 1 C) 37.00(s, 1 C) 39.68 (s, 1 C) 56.03 (s, 1 C) 57.17 (s, 1 C) 93.91 (S, 1 C)108.75 (s, 1 C) 118.19 (s, 1 C) 134.06 (s, 1 C) 155.42 (S, 1 C) 157.32(s, 1 C) 170.21 (s, 1 C).

Example 10

N-(2-(2,6-dimethoxy-1H-benzimidazol-1-yl)ethyl) acetamide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)acetamide (Example 1 (B))(550 mg, 2.46 mmol), tetramethylorthocarbonate, (1.34 g, 9.85 mmol) andsubsequently acetic acid (0.015 g, 0.250 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (25 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (25 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin a white solid product. (m=344 mg. Yield: 53%)

¹H NMR (300 MHz, CHLOROFORM-d) δppm 1.92 (s, 3H) 3.57 (q, J=5.92 Hz, 2H)3.83 (s, 3H) 4.06-4.13 (m, 5H) 5.83 (br s, 1H) 6.72 (d, J=2.68 Hz, 1H)6.75-6.81 (m, 1H) 7.40 (d, J=8.62 Hz, 1H); ¹³C NMR (75 MHz,CHLOROFORM-d) δppm 23.13 (s, 1 C) 38.96 (s, 1 C) 41.24 (s, 1 C) 55.99(s, 1 C) 57.02 (s, 1 C) 93.45 (s, 1 C) 109.32 (s, 1 C) 118.16 (s, 1 C)133.82 (s, 1 C) 134.56 (s, 1 C) 155.61 (s, 1 C) 157.34 (s, 1 C) 170.69(s, 1 C) Example 11

N-(2-(2,6-dimethoxy-1H-benzimidazol-1-yl)ethyl)propionamide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)propionamide (Example 2 (B))(200 mg, 0.84 mmol), tetramethylorthocarbonate(0.460 g, 3.37 mmol) andsubsequently acetic acid (0.010 g, 0.167 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (10 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (10 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin a white solid product. (m=129 mg. Yield: 55%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.10 (t, J=7.63 Hz, 3H) 2.13 (q,J=7.63 Hz, 2H) 3.58 (q, J=5.85 Hz, 2H) 3.68-3.88 (m, 3H) 3.97-4.17 (m,5H) 5.66 (br s, 1H) 6.71 (d, J=2.44 Hz, 1H) 6.78 (dd, J=8.54, 2.44 Hz,1H) 7.42 (d, J=8.70 Hz, 1H) Example 12

N-(2,6-dimethoxy-1H-benzimidazol-1-yl)ethyl)butyramide

In a 10 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)butyramide (Example 3 (B))(100 mg, 0.398 mmol), tetramethylorthocarbonate(0.217 g, 1.59 mmol) andsubsequently acetic acid (0.024 g, 0.0398 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (5 ml) was added. The precipitated solid was filtered, washed withethyl ether (5 ml) and purified by MPLC (CHC13:MeOH 9:1) resulting in awhite solid product. (m=55.6 mg. Yield: 48%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 0.91 (t, J=7.40 Hz, 3H) 1.68-1.75(m, 2H) 2.08 (t, J=7.55 Hz, 2H) 3.44-3.64 (m, 2H) 3.71-3.88 (m, 3H)4.04-4.17 (m, 6H) 5.65 (br s, 1H) 6.72 (d, J=2.44 Hz, 1H) 6.78 (dd,J=8.70, 2.44 Hz, 1H) 7.42 (d, J=8.70 Hz, 1H)

Example 13

N-(1-(2-Ethoxy-6-methoxy-1H-benzimidazol-1-yl)propan-2-yl) acetamide

(A) N¹-(5-methoxy-2-nitrophenyl)propane-1,2-diamine

In a 10 ml reactor with magnetic stirring, 3-chloro-4-Nitroanisole (0.5g, 2.67 mmol), 1,2-propanediamine (3 ml, 35.2 mmol) and cupric bromide(0.250 g, 1.12 mmol) were added. The reaction medium was kept understirring and heating at 60-65° C. for 1 hour. After cooling, thereaction medium was diluted with water and extracted three times withchloroform. The organic phases were combined and washed with water. Thechloroform was dried over magnesium sulfate and roto-evaporated todryness resulting in a yellow colored solid which was used directly inthe next step. (m=0.60 g. Yield: 100%)

(B) N-(1-((5-methoxy-2-nitrophenyl)amino)propan-2-yl)acetamide

In a 50 ml reactor N1-(5-methoxy-2-nitrophenyl) propane-1,2-diamine(0.60 g, 2.67 mmol), ethanol (40 ml) and acetic anhydride (0.254 ml,2.67 mmol) were added. The reaction medium was heated to 60° C. and keptunder stirring for 1 hour. Then the ethanol was evaporated to drynessand the resulting oil dissolved in ethyl acetate and washed with 15%sodium carbonate solution. The organic phase was separated, dried withmagnesium sulfate and roto-evaporated resulting in a yellow solidproduct, which was employed directly in the next step. (m=0.55 g. Yield:77%) (C) N-(1-((2-amino-5-methoxyphenyl)amino)propan-2-yl)acetamide

In a 100 ml reactor, N-(1-((5-methoxy-2-nitrophenyl)amino)propan-2-yl)acetamide (0.55 g, 2.06 mmol) and methanol (35 ml) were added. Thesystem was kept under stirring with heating between 40 and 50° C. untilcomplete dissolution of the solid. Then the reaction medium was cooledto room temperature and powdered zinc (2.0 g, 30.6 mmol) and ammoniumformate (0.97 g, 15.4 mmol) were added under vigorous stirring. Theresulting mixture was kept under stirring for approximately 30 minutesand then gravity filtered. The filtrate was roto-evaporated and theresulting residue was extracted with dichloromethane (300 ml). Thedichloromethane was washed with 6N sodium hydroxide solution (2×200 ml)and sodium chloride solution(300 ml). The organic phase was separated,dried with magnesium sulfate and roto-evaporated yielding the product asoil, which was used directly in the next step. (m=0.41 g Yield: 84%)

(D) N-(1-(2-Ethoxy-6-methoxy-1H-benzimidazol-1-yl)propan-2-yl) acetamide

In a 50 ml reactor containingN-(1-((2-amino-5-methoxyphenyl)amino)propan-2-yl)acetamide (400 mg, 1.69mmol), tetraethyl orthocarbonate (1.3 g, 6.7 mmol) and subsequentlyacetic acid (0.010 g, 0.169 mmol) were added. The reaction was heated to80° C. and kept at this temperature for 30 min. Then the reaction mediumwas allowed to return to room temperature and ethyl ether (25 ml) wasadded. The precipitated solid was filtered, washed with ethyl ether (25ml) and purified by MPLC (CHC13:MeOH 9:1) resulting in a white solidproduct. (m=240 mg. Yield: 49%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.18 (d, J=6.87 Hz, 3H) 1.44-1.54(m, 5H) 1.94 (s, 3H) 3.83-3.90 (m, 4H) 3.97-4.07 (m, 2H) 4.31-4.39 (m,1H) 4.47-4.69 (m, 3H) 5.51 (br d, J=7.17 Hz, 1H) 6.74-6.79 (m, 1H) 6.88(d, J=2.44 Hz, 1H) 7.40 (d, J=8.55 Hz, 1H)

Example 14

2-Bromo-N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl) acetamide

(A) 2-bromo-N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)acetamide

In a 100 ml reactor with magnetic stirring, N1-(5-methoxy-2-nitrophenyl)ethane-1,2-diamine (1 g, 4.73 mmol), dichloromethane (50 ml) andtriethylamine (0.67 ml, 4.81 mmol) were added. The reaction medium waskept under stirring and a bromoacetyl bromide solution (0.413 ml, 4.74mmol) in dichloromethane (10 ml) was slowly added through an additionfunnel. The reaction medium was kept under stirring at room temperaturefor 2 hours. After the completion of the reaction, 10 ml of 10% aqueoushydrochloric acid solution (10 ml) was added. The dichloromethane wasseparated and the aqueous phase extracted with dichloromethane (2×20ml). The organic phase was washed with 5% aqueous bicarbonate solution(100 ml) and saturated sodium chloride solution (100 ml). The organicextract was separated, dried with anhydrous magnesium sulfate androto-evaporated, resulting in a yellow solid product which was useddirectly in the next step. (m=1.45 g. Yield: 92%)

(B) N-(2-((2-amino-5-methoxyphenyl)amino)ethyl)-2-bromoacetamide

In a 100 ml reactor,2-bromo-N-(2-((5-methoxy-2-nitrophenyl)amino)ethyl)acetamide (0.70 g,2.31 mmol) and methanol (50 ml) were added. The system was kept understirring with heating between 40 and 50° C. until complete dissolutionof the solid. Then the reaction medium was cooled to room temperatureand powdered zinc (2.05, 31.4 mmol) and ammonium formate (1.0 g, 15.9mmol) were added under vigorous stirring. The resulting mixture was keptunder stirring for approximately 30 minutes and then gravity filtered.The filtrate was roto-evaporated and the resulting residue was extractedwith 350 ml of dichloromethane. The dichloromethane was washed with 6Nsodium hydroxide solution (2×200 ml) and sodium chloride solution (300ml). The organic phase was separated, dried with magnesium sulfate androto-evaporated resulting in a product as oil, which was used directlyin the next step. (m=0.57 g. Yield: 90%)

(C) 2-Bromo-N-(2-(2-ethoxy-6-methoxy-1H-benzimidazol-1-yl)ethyl)acetamide

In a 50 ml reactor containingN-(2-((2-amino-5-methoxyphenyl)amino)ethyl)-2-bromoacetamide (570 mg,1.89 mmol), tetraethyl orthocarbonate (1.45 g, 7.5 mmol) andsubsequently acetic acid (0.113 g, 0.189 mmol) were added. The reactionwas heated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (25 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (25 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin a white solid product. (m=362 mg. Yield: 54%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.40-1.50 (m, 3H) 3.58-3.70 (m, 2H)3.71-3.87 (m, 6H) 3.94-4.16 (m, 2H) 4.55-4.62 (m, 2H) 6.62-6.70 (m, 1H)6.72 (d, J=2.44 Hz, 1H) 6.78 (d, J=8.27 Hz, 1H) 7.42 (d, J=8.70 Hz, 1H)Example 15

N-(2-(6-methoxy-2-(methylthio)-1H-benzimidazol-1-yl)ethyl) acetamide

(A) N-(2-(2-mercapto-6-methoxy-1H-benzimidazol-1-yl)ethyl) acetamide

In a 10 ml reactor N-(2-((2-amino-5-methoxyphenyl)amino)ethyl)acetamide(1.340 g, 6.00 mmol) and thiourea (0.457 g, 6.00 mmol) were added. Themixture was initially heated to 120° C. for 10 min with intense vaporrelease and then heated to 160° C. for 5 min, with second vapor release.The temperature was reduced to 80° C. and ethanol (15 ml) was added. Theresulting mixture was cooled to −10° C., the solid filtered and washedwith ice cold ethanol (10 ml), yielding 1.26 g (79%) of the crudeproduct, which was purified by MPLC (CHC13/MeOH 9:1) resulting the titlecompound as a rosy solid. (m=1.1 g. Yield: 69.1%)

(B) N-(2-(6-methoxy-2-(methylthio)-1H-benzimidazol-1-yl)ethyl) acetamide

Potassium carbonate (13.02 mg, 0.094 mmol) followed by iodomethane(5.891, 0.094 mmol) were added to a solution ofN-(2-(2-mercapto-6-methoxy-1H-benzimidazol-1-Yl)ethyl)acetamide (50.0mg, 0.188 mmol) in acetone (2 ml) at 0° C. The reaction was kept understirring at room temperature for 1 h. After, a second portion ofpotassium carbonate (13.02 mg, 0.094 mmol) and iodometane (5.891a, 0.094mmol) were added and the mixture remained under stirring overnight atroom temperature. Volatile portion was removed under reduced pressureand the residue partitioned between ethyl acetate (10 ml) and water (10ml). The organic extract was separated, dried with magnesium sulfate andevaporated under reduced pressure to yield the pure product. (m=44 mg.Yield: 84%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.93 (s, 3H) 2.76 (s, 3H) 3.61 (q,J=5.95 Hz, 2H) 3.82-3.86 (m, 3H) 4.24 (t, J=5.80 Hz, 2H) 6.79 (s, 1H)6.84 (d, J=8.76 Hz, 1H) 7.27 (s, 1H) 7.54 (d, J=8.70 Hz, 1H) Example 16

N-(2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)acetamide

(A)tert-Butyl(2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)carbamate

In a 25 ml reactor containingtert-butyl(2-((5-amino-2,3-dihydrobenzofuran-4-yl)amino)ethyl) carbamate(200 mg, 0.682 mmol), tetraethyl orthocarbonate (524 mg, 2.727 mmol)followed by acetic acid (4 mg, 0.038 mmol) were added. The reaction washeated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (10 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (10 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin a white solid product. (m=181 mg. Yield: 76%)

(B) 2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethanamine

In a 25 ml reactor,tert-Butyl(2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)carbamate(150 mg, 0.432 mmol) were dissolved in 6 ml dichloromethane. Nexttrifluoroacetic acid (0.266 ml, 3.451 mmol) was added. The reaction wasstirred at room temperature for 6 h (monitored by HPLC). After thereaction was complete, the reaction medium was transferred to a beakerand diluted with dichloromethane (50 ml). A 15% aqueous sodium carbonatesolution was added under vigorous stirring until pH=12. The organicphase was separated, dried with magnesium sulfate and evaporatedresulting in a white solid product, which was used directly in the nextstep. (m=80 mg. Yield: 75%)

(C) N-(2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)acetamide

In a 25 ml reactor, ethanol (10 mg),2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethanamine (70mg, 0.283 mmol), acetic anhydride (0.030 ml, 0.3.11 mmol) and sodiumcarbonate (33 mg, 0.311 mmol) were added. The reaction mixture washeated under reflux for 1 h and then evaporated under reduced pressure.The resulting oil was dissolved in ethyl acetate (30 ml) and washed with10% aqueous sodium carbonate solution (10 ml). The organic extract wasdried over magnesium sulfate, roto-evaporated and the resulting solidpurified by chromatography (MPLC) (CHC13:MeOH 9:1) resulting in a whitesolid product. (m=75 mg. Yield: 92%) ¹H NMR (300 MHz, CHLOROFORM-d) δppm1.44 (t, J=7.09 Hz, 3H) 1.86-1.97 (m, 3H) 3.38-3.65 (m, 5H) 4.11 (t,J=6.11 Hz, 2H) 4.45-4.72 (m, 4H) 5.92 (br s, 1H) 6.68 (d, J=8.46 Hz,1H);

¹³C NMR (75 MHz, CHLOROFORM-d) δppm 14.76 (s, 1 C) 23.12 (s, 1 C) 28.09(s, 1 C) 39.82 (s, 1 C) 41.98 (s, 1 C) 66.15 (s, 1 C) 71.43 (s, 1 C)103.82 (s, 1 C) 106.28 (s, 1 C) 116.53 (s, 1 C) 130.54 (s, 1 C) 134.43(s, 1 C) 156.53 (s, 1 C) 156.68 (s, 1 C) 170.59 (s, 1 C).

Example 17

N-(2-(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)acetamide

(A) tert-Butyl(2-(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)carbamate

In a 10 ml reactor containing tert-butyl(2-((5-amino-2,3-dihydrobenzofuran-4-yl)amino)ethyl)carbamate (200 mg,0.682 mmol), tetramethylorthocarbonate (374 mg, 2.728 mmol) andsubsequently acetic acid (4 mg, 0.038 mmol) were added. The reaction washeated to 80° C. and kept at this temperature for 30 min. Then thereaction medium was allowed to return to room temperature and ethylether (10 ml) was added. The precipitated solid was filtered, washedwith ethyl ether (10 ml) and purified by MPLC (CHC13:MeOH 9:1) resultingin white solid a product. (m=160 mg. Yield: 70%) (B)2-(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d] imidazol-1-yl)ethanamine

In a 25 ml reactor,tert-Butyl(2-(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)carbamate(113 mg, 0.399 Mmol) was added to 5 ml dichloromethane. Thentrifluoroacetic acid (0.209 ml, 2.71 mmol) was added. The reaction wasstirred at room temperature for 6 h (monitored by HPLC). After thereaction was complete, the reaction medium was transferred to a beakerand diluted with dichloromethane (50 ml). A 15% aqueous sodium carbonatesolution was added Under vigorous stirring until pH=12. The organicphase was separated, dried with magnesium sulfate and evaporatedresulting in a white solid product, which was used directly in the nextstep. (m=55 mg. Yield: 69.6%)

(C)N-(2-(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazol-1-yl)ethyl)acetamide

In a 25 ml reactor, ethanol (10 ml),2-(2-methoxy-7,8-dihydro-1H-benzofuran [4,5-d]imidazol-1-yl) ethanamine(55 mg, 0.236 mmol), acetic anhydride (0.025 ml, 0.259 mmol) and sodiumcarbonate (27.5 mg, 0.258 mmol) were added. The reaction mixture washeated under reflux for 1 h and then evaporated under reduced pressure.The obtained oil was dissolved in ethyl acetate (30 ml) and washed with10% aqueous sodium carbonate solution (10 ml). The organic extract wasdried over magnesium sulfate, roto-evaporated and the resulting solidwas purified by chromatography (MPLC) (CHC13:MeOH 9:1) resulting in awhite solid product. (m=58 mg. Yield: 89%) ¹H NMR (300 MHz,CHLOROFORM-d) δppm 1.95 (s, 3H) 3.38-3.61 (m, 5H) 4.06-4.13 (m, 6H) 4.63(t, J=8.59 Hz, 2H) 5.95 (br s, 1H) 6.68 (d, J=8.44 Hz, 1H);

¹³C NMR (75 MHz, CHLOROFORM-d) δppm 23.10 (s, 1 C) 28.05 (s, 1 C) 39.74(s, 1 C) 42.02 (s, 1 C) 57.02 (s, 1 C) 71.45 (s, 1 C) 103.87 (s, 1 C)106.33 (s, 1 C) 116.64 (s, 1 C) 130.76 (s, 1 C) 134.30 (s, 1 C) 156.77(s, 1 C) 157.13 (s, 1 C) 170.67 (s, 1 C).

Example 18

N-(2-(5-bromo-2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl) acetamide

In a 10 ml reactor,N-(2-(2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl)acetamide(Example 1) (100 mg, 0.360 mmol), chloroform (5 ml) andN-bromosuccinimide (64 mg, 360 mmol) were added. The reaction medium wasunder reflux and kept under stirring for 8 hours. The reaction mediumwas diluted with chloroform (50 ml), the organic phase was washed with5% aqueous sodium carbonate solution (3×30 ml), dried with magnesiumsulfate, roto-evaporated and purified by chromatography resulting in awhite solid product. (m=70 mg. Yield: 54%)

1H NMR (500 MHz, CHLOROFORM-d) δppm 1.46 (t, J=7.10 Hz, 3H) 1.89-1.93(m, 3H) 3.56 (q, J=5.95 Hz, 2H) 3.88-3.92 (m, 3H) 4.13 (t, J=5.87 Hz,2H) 4.51-4.59 (m, 2H) 5.71 (br s, 1H) 6.79 (s, 1H) 7.67 (s, 1H) Example19

N-(2-(5-chloro-2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl) acetamide

In a 50 ml reactorN-(2-(2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl)acetamide(Example 1) (0.5 g, 1.80 mmol), isopropanol (25 ml) andN-chlorosuccinimide (0.241 g, 1.80 mmol) were added. The reaction mediumwas under reflux and kept under heating and stirring for 24 hours. Afterthe reaction was complete, the reaction medium was roto-evaporated todryness and diluted with chloroform (200 ml). The chloroform was washedwith 5% aqueous sodium carbonate solution (3×150 ml), dried withanhydrous magnesium sulfate and roto-evaporated. The residue containingthe raw product was purified by chromatography resulting in a whitesolid product. (m=345 mg. Yield: 61%)

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.44-1.50 (m, 3H) 1.89-1.93 (m, 3H)3.47-3.72 (m, 2H) 3.89-3.93 (m, 3H) 4.12 (t, J=5.87 Hz, 2H) 4.44-4.68(m, 2H) 7.27 (s, 1H) 7.50 (s, 1H);

¹³C NMR (75 MHz, CHLOROFORM-d) δppm 14.70 (s, 1 C) 23.17 (s, 1 C) 39.02(s, 1 C) 41.13 (s, 1 C) 56.95 (s, 1 C) 66.41 (s, 1 C) 93.00 (s, 1 C)116.67 (s, 1 C) 118.99 (s, 1 C) 133.00 (s, 1 C) 133.82 (s, 1 C) 150.76(s, 1 C) 157.05 (s, 1 C) 170.76 (s, 1 C).

Example 20

N-(3-(5-chloro-2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)propyl)acetamide

In a 10 ml reactor,N-(3-(2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)propyl)acetamide (Example8) (50 mg, 0.172 mmol), N-chlorosuccinimide (23 mg, 0.172 mmol) andisopropanol (2 ml) were added. The reaction medium was kept under refluxand stirred for 18 hours, then poured into chloroform (40 ml). Theorganic phase was washed with 5% aqueous sodium carbonate solution (3×20ml), dried with magnesium sulfate, roto-evaporated and the residuepurified by flash chromatography resulting in a white solid. (m=42 mg.Yield: 75%).

¹H NMR (300 MHz, CHLOROFORM-d) δppm 1.49 (t, J=7.09 Hz, 3H) 1.94-2.03(m, 5H) 3.26 (q, J=6.68 Hz, 2H) 3.92-4.03 (m, 5H) 4.59 (q, J=7.12 Hz,2H) 5.58 (br s, 1H) 6.72 (s, 1H) 7.53 (s, 1H);

¹³C NMR (75 MHz, CHLOROFORM-d) δppm 14.74 (s, 1 C) 23.30 (s, 1 C) 28.73(s, 1 C) 36.91 (s, 1 C) 39.70 (s, 1 C) 57.10 (s, 1 C) 66.47 (s, 1 C)93.23 (s, 1 C) 116.80 (s, 1 C) 119.13 (s, 1 C) 132.36 (s, 1 C) 134.12(s, 1 C) 150.68 (s, 1 C) 157.06 (s, 1 C) 170.18 (s, 1 C).

Example 21

N-(3-(5-chloro-2,6-dimethoxy-1H-benzimidazole-1-yl) propyl)acetamide

In a 10 ml reactor, N-(3-(2,6-dimethoxy-1H-benzimidazole-1-yl)propyl)acetamide (Example 9) (48.5 mg, 0.175 mmol), N-chlorosuccinimide (24.1mg, 0.180 mmol) and isopropanol (2 ml) were added. The reaction mediumwas kept under reflux and stirred for 6 hours, then poured intochloroform (40 ml). The organic phase was washed with 5% aqueous sodiumcarbonate solution (3×20 ml), dried with magnesium sulfate,roto-evaporated and the residue purified by chromatography resulting ina white solid. (m=37 mg. Yield: 68%).

¹H NMR (500 MHz, CHLOROFORM-d) δppm 1.82-2.13 (m, 5H) 3.27 (q, J=6.82Hz, 2H) 3.84-3.94 (m, 3H) 3.99 (t, J=6.87 Hz, 2H) 4.11-4.19 (m, 3H) 5.54(br s, 1H) 6.72 (s, 1H) 7.54 (s, 1H) Example 22

N-(2-(5-chloro-2,6-dimethoxy-1H-benzimidazole-1-yl)ethyl) acetamide

In a 10 ml reactor,N-(2-(2,6-dimethoxy-1H-benzimidazole-1-yl)ethyl)acetamide (Example 10)(60 mg, 0.228 mmol), N-chlorosuccinimide (30.4 mg, 0.228 mmol) andisopropanol (3 ml) were added. The reaction medium was kept under refluxand stirred for 96 hours, then poured into chloroform (40 ml). Theorganic phase was washed with 5% aqueous sodium carbonate solution (3×20ml), dried with magnesium sulfate, roto-evaporated and the residuepurified by flash chromatography resulting in a white solid. (m=18 mg.Yield: 27%)

¹H NMR (300 MHz, CHLOROFORM-d) δppm 1.88-1.96 (m, 3H) 3.52-3.68 (m, 2H)3.92 (s, 3H) 4.09-4.17 (m, 5H) 6.80 (s, 1H) 7.52 (s, 1H); ¹³C NMR (75MHz, CHLOROFORM-d) δppm 23.16 (s, 1 C) 39.02 (s, 1 C) 41.14 (s, 1 C)56.94 (s, 1 C) 57.25 (s, 1 C) 93.02 (s, 1 C) 116.74 (S, 1 C) 119.10 (S,1 C) 133.18 (s, 1 C) 133.66 (s, 1 C) 150.85 (S, 1 C) 157.61 (s, 1 C)170.83 (s, 1 C). Example 23

N-(2-(5-chloro-2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl)cyclopropanecarboxamide

In a 10 ml reactor,N-(2-(2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl)cyclopropanecarboxamide (Example 4) (92 mg, 0.329 mmol), N-Chlorosuccinimide (45 mg,0.337 mmol) and isopropanol (4 ml) were added. The reaction medium waskept under reflux and stirred for 24 hours, then poured into chloroform(60 ml). The organic phase was washed with 5% aqueous sodium carbonatesolution (3×30 ml), dried with magnesium sulfate, roto-evaporated andthe residue purified by chromatography resulting in a white solid. (m=61mg. Yield: 60%).

¹H NMR (500 MHz, CHLOROFORM-d) δppm 0.66-0.85 (m, 2H) 0.87-1.02 (m, 2H)1.20-1.34 (m, 1H) 1.46 (t, J=7.10 Hz, 3H) 3.57-3.74 (m, 2H) 3.89-3.98(m, 3H) 4.11 (t, J=5.80 Hz, 2H) 4.45-4.66 (m, 2H) 6.76 (s, 1H) 7.27 (s,1H) 7.50 (s, 1H).

Example 24

N-(2-(7-chloro-2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl) acetamide

In a 125 ml reactor,N-(2-(2-ethoxy-6-methoxy-1H-benzimidazole-1-yl)ethyl)acetamide(Example 1) (0.5 g, 1.80 mmol), chloroform (50 ml) andN-chlorosuccinimide (0.270 g, 2.02 mmol) were added. The reaction mediumwas under reflux and kept under heating and stirring for 48 hours. Afterthis period, the reaction medium was roto-evaporated to dryness anddiluted with chloroform (200 ml). The chloroform was washed with 5%aqueous sodium carbonate solution (3×150 ml), dried with anhydrousmagnesium sulfate and roto-evaporated. The residue was fractionated bychromatography resulting in a white solid product. (m=128 mg. Yield:23%).

¹H NMR (300 MHz, DMSO-d₆) δppm 1.38 (t, J=6.97 Hz, 3H) 1.74 (s, 3H)3.33-3.40 (m, 3H) 3.84 (s, 3H) 4.28 (t, J=5.87 Hz, 2H) 4.47 (q, J=7.09Hz, 2H) 6.93 (d, J=8.44 Hz, 1H) 7.31 (d, J=8.80 Hz, 1H) 7.99 (br t,J=5.87 Hz, 1H);¹³C NMR (75 MHz, DMSO-d₆) δppm 14.41 (s, 1 C) 22.45 (s, 1 C) 42.15 (s, 1C) 56.94 (s, 1 C) 66.07 (s, 1 C) 102.83 (s, 1 C) 106.80 (s, 1 C) 115.80(s, 1 C) 130.18 (s, 1 C) 135.87 (s, 1 C) 149.98 (s, 1 C) 157.30 (s, 1 C)169.44 (s,1 C).

2. Tests Conducted and Test Results

The examples described herein are for the sole purpose of exemplifyingone of a number of ways of carrying out the invention, but are notlimited to the scope thereof.

Description of Tables

Table 1: Binding and functional assays results on melatonergic receptorsMT1 and MT2 for selected compounds.Table 2: Permeability study results onCaco-2 cells (10-6 cm/s).Table 3: Water solubility study results, expressed as μM.Table 4: Intrinsic clearance study results on cryopreserved humanhepatocytes, expressed as half-life (minutes).Table 5: Results for the inhibition study in human recombinantcytochromes (CYP), expressed as percent inhibition (%).Table 6: Pharmacokinetic profile study results in CD-1 mice andWistar-Han mice after oral (10 mg/kg) and intravenous (1 mg/kg)administration of the compounds.

2.1—MT1 and MT2—Binding

The binding assay was performed in melatonergic MT1 and MT2 receptors inorder to check the receptor affinity for the ligand, i.e., the abilityof the molecule to bind to the respective receptors. The Ki described inthe results is the dissociation constant and measures the affinity of anon-radioactive test compound for the receptor. The IC50 shows theconcentration of the substance required for achieving 50% inhibition ofthe receptors. Kd shows the affinity of the radio ligand to thereceptor. Receptor inhibition is measured by the % of inhibition abinding specific control. Recombinant human cells (CHO-derived) and[1251]2-iodomelatonin compound labeling were used followed by incubationand detection at concentration of 0.01-0.05 nM by Scintillation Count,with Kd 0.04 nM and 0.085 nM, respectively. Incubation was performed for60-120 min at 37° C.

According to the results, agomelatine showed high affinity to themelatonergic receptor MT1 (Ki 0.2 nM) and MT2 (Ki 0.042 nM). Theinventive compounds also showed high affinity for both MT1 and MT2receptors, as demonstrated in Table 1. The affinity of compounds 120,121, 140, 142 and 143, expressed as affinity constant (Ki) values by theMT1 receptor was 1.1, 0.88, 2.2, 1.3 and 2.1 nM. The affinity for theMT2 receptor was 4.5, 0.93, 11, 1.6 and 0.8 nM, respectively.

TABLE 1 MT1 MT2 MT1 MT2 Functional Functional Compound Binding BindingEC50 EC50 Chemical structure code Ki (nM) Ki (nM) (nM) (nM)

IA2-76 (agomelatine) 0.2 0.042 0.15 0.019

IA2-120 1.1 4.5 0.19 0.38

IA2-121 0.88 0.93 0.16 0.25

IA2-140 2.2 11 2.1 1.2

IA2-142 13 1.6 3.4 0.39

IA2-143 2.1 0.8 0.25 2.8

2.2—MT1 or MT2—Functional

Functional results are assays that allow the determination of theintrinsic activity of drugs, indicating whether a compound is anagonist, antagonist or inverse agonist. The EC50 shows the drugconcentration required to induce half the maximal effect, after aspecific exposure time, and is usually used as way to measure thepotency of a drug. As an example, we can mention the use of HEK-293 as arecombinant cell in which a specific stimulus was performed (accordingto the drug/compound in study), followed by incubation. The detection ofthe result was carried out by Cellular Dielectric Spectroscopy forimpedances or by HTRF (Homogeneous Time Resolved Fluorescence) to detectIP1 (myo-Inositol 1 phosphate), a protein related to intracellularsignaling.

According to the results from the assay, agomelatine behaves as anagonist and showed high potency for the MT1 receptors (EC50 0.15 nM) andMT2 (EC50 0.019 nM). The inventive compounds also behave as agonists anddemonstrated high potency to the melatonergic receptors MT1 and MT2, asshown in Table 1. The potency of compounds 120, 121, 140, 142 and 143for the MT1 receptor, expressed as EC50, was 0.19, 0.16, 2.1, 3.4, 0.25nM. And the potency of the same compounds for the MT2 receptor was 0.38,0.25, 1, 2, 0.39 and 2.8 nM, respectively, demonstrating that compounds120, 121 and 143 have higher potency for MT1 with respect to MT2 andcompounds 140 and 142 show higher potency for MT2 with respect to MT1.

2.3—Permeability

Permeability tests were performed using Caco-2 cells, a colorectalepithelial adenocarcinoma cell line. These cells resemble intestinalepithelial cells in some aspects, such as the formation of a polarizedmonolayer, a well-defined brush border on the apical surface, andintercellular junctions.

The test is performed in both directions [apical to basolateral (A-B)and basolateral to apical (B-A)] through the cell monolayer, allowing anefflux ratio that provides an indicator as to whether a compoundundergoes active efflux. Particle detection was performed withHPLC-MS/MS (mass spectrometry) according to the calculation of the peakarea of the result. MS/MS was performed by combining two mass detectorsin a single instrument.

A-B permeability was performed at pH 6.5/7.4 with incubation time of 0and 60 minutes at 37° C. and B-A permeability was performed at pH6.5/7.4 with incubation time of 0 and 40 minutes at 37° C.

The results in Table 2 show that the test compounds presented goodpermeability rate (>10-6 cm/s) in Caco-2 cells.

TABLE 2 Permeability Permeability A-B (pH B-A (pH Chemical StructureMolecule Code 6.5/7.4) 6.5/7.4)

IA2-76 (agomelatine) 83.9 48.5

IA2-120 32.1 29.5

IA2-121 58.2 32.1

IA2-140 27.3 55.1

IA2-142 34.0 57.8

IA2-143 21.3 71.8

2.4—Water Solubility

Water solubility of the present invention was determined by comparingthe peak area calculation in a calibration standard (200 μM) containingorganic solvent (methanol/water, 60/40, v/v) with the area calculationof the corresponding peak in a buffer sample. In addition,chromatographic purity (%) was defined as the calculation of the mainpeak area relative to the calculation of the peak area integrate of thestandard HPLC calibration chromatogram. A standard calibrationchromatogram was then generated for each compound tested along with aUV/VIS spectrum with maximal labeled absorbance. The shake-flashtechnique was used with constant stirring during incubation to keep auniform medium for 24 hours in PBS at pH 7.4. The results showed thatthe solubility of the test compounds was similar to that of agomelatine,as shown in Table 3.

TABLE 3 Mole- PBS, cule pH 7.4 Chemical Structure Code (μM)

IA2-76 (ago- melatine) 196

IA2-120 200

IA2-121 200

IA2-140 197.2

IA2-142 180.8

IA2-143 196.7

2.5—Intrinsic Clearance in Human Hepatocytes

Cryopreserved hepatocytes from humans, rats (Sprague-Dawley males) andfrom mice (CD-1 males) were used for incubation at different times (0,0.5, 1, 1.5, 2 hours) at 37° C. followed by HPLC-MS/MS detection. Theaim was to verify the clearance time of the test substance onhepatocytes. The experiment was performed on a 96-well plate and thecryopreserved hepatocytes were thawed and resuspended in Krebs-Heinsletbuffer (pH 7.3). The reaction was started by adding each test compoundto each cell suspension and performing the incubation at the timesindicated above. The reaction was quenched with addition of acetonitrilein the wells and detection by HPLC-MS/MS (mass spectrometry). MS/MS isperformed by combining two mass detectors into a single instrument.

The half-life expressed in minutes for intrinsic clearance in humanhepatocytes was greater than 120 minutes for all inventive compounds,while agomelatine had a clearance half-life of 48 minutes, as shown inFIG. 5. Similar results were seen with the compounds 120 and 121 in CD-1mice and in Sprague-Dawley rats, compounds 120 and 121 presentedclearance half-lives of 53 and 52 minutes, respectively, compared to 50minutes for agomelatine (Table 4).

TABLE 4 Rat Sprague- Mouse Chemical Structure Molecule Code Human DawleyCD-1

IA2-76 (agomelatine) 48 50 25

IA2-120 >120 53 >120

IA2-121 >120 52 >120

IA2-140 >120 >120.0 >120

IA2-142 >120 >120.0 >120

IA2-143 >120 108 >120

2.6—Inhibition of CYP

The CYP inhibition test used fluorogenic substrates specific to each CYPto check for inhibition thereof by detection of the expected metaboliteusing a fluorimetric method. Recombinant CYPs (CYP2B6, CYP2C8, CYP2C9,CYP2C9, CYP2C19, CYP2D6, CYP3A4) from specific humans for eachcytochrome family, subfamily and polypeptide were used. The followingwere used as substrates: CEC (3-Cyano-7-Ethoxycoumarin) which forms asmetabolite CHC (3-Cyano-7-Hydroxycoumarin); EFC(7-Ethoxy-4-trifluoromethyl coumarin), forming the metabolite HFC(7-Hydroxytrifluoromethylcoumarin); DBF (Dibenzylfluorescein) and itsrespective fluorescein metabolite; MFC(7-Methoxy-4-trifluoromethylcoumarin) which forms the metabolite HFC(7-Hydroxytrifluoromethylcoumarin); BFC(7-Benzyloxy-Trifluoromethylcoumarin) and its metabolite HFC; and BzRes(benzyloxyresorufin) to form resofurine. The detection of the metabolitewas done with a fluorimetric method: analytical technique to identifyand characterize the amount of substance by excitation using a beam ofultraviolet light and measurement of the emitted fluorescence. Fordetection, a 96-well plate was used. Each sample was tested in two wells(n=2) as standard condition. At least 04 wells were separated forvehicle (control). Compounds were tested at a concentration of 10 μM,standard for this assay. They were preincubated with a NADPH generatorsystem in a phosphate buffer (pH 7.4) for 5 minutes at 37° C. Thereaction was started by adding the specific CYP enzymes, substrate andbovine serum albumin (BSA<0.4 mg/ml). Incubations were performed between20-50 minutes at 37° C. according to the specific parameter of eachfluorogenic substrate, for the evaluated component. Fluorescence at eachwell was detected before and after the incubation period.

The results demonstrated that the inventive compounds do not presenthigh affinity to the 07 cytochrome isoforms analyzed (CYP2A6, CYP2B6,CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4), specially to CYP1A2, CYPisoform which agomelatine has high affinity, according to Table 5.

TABLE 5 CYP1A2 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP3A4 CYP3A4Chemical Structure Code Inhibition Inhibition Inhibition InhibitionInhibition Inhibition Inhibition * Inhibition **

IA2-76 79.8 1.8 12.9 −19.3 44.4 7.9 21.6 −0.8

IA92-120 −8.2 7.9 9.1 26.7 6.4 −0.3 15.7 8.3

IA2-121 10.5 8.4 7 23.7 33.8 0.9 15.3 −5.4

IA2-140 −0.7 0.4 −2.2 2.6 7.2 0.3 5.6 21.2

IA2-142 12.1 0.5 −4.7 13.0 27.7 6.9 −1.6 −17.6

IA2-143 1.4 −1.1 −13.0 −9.6 10.0 0.8 2.1 15.9

2.7—Pharmacokinetics (PK) in Mouse—I.V. And Oral

PK tests were performed with CD-1 mice, using 4 animals per moleculetested, 2 animals for pharmacokinetic analysis by intravenous (IV)administration and 2 animals for oral administration. The treatment wascarried out in a single dose: I.V. group with dose of 1 mg/kg and Oralgroup with dose of 10 mg/kg. The vehicle consisted of 5 DMSO, 30% PEG400and 65% water. Blood collection was performed after euthanasia at 08defined time points and at 24 hours post-dose. The pharmacokineticanalysis parameters detected for Group IV were: half-life (t1/2), drugconcentration at time zero (C0), last measurable plasma concentration(AUClast), area under the plasma concentration curve extrapolationpercentage (AUC % ext), area under the plasma concentration curveextrapolation to infinity (AUCinf), volume of distribution (Vz), steadystate volume of distribution (Vss), clearance (CL) and mean residencetime (MRT). The parameters evaluated for the Oral group were:bioavailability (F %), maximum concentration reached (Cmax), time toreach maximum plasma concentration (Tmax), last measurable plasmaconcentration (AUClast), area under the plasma concentration curveextrapolation percentage (AUC % ext), area under the plasmaconcentration curve extrapolation to infinity (AUCinf), area under theplasma concentration curve extrapolation to infinity versus dose(AUCinf/Dose), half-Life (t1/2), and mean residence time (MRT).

After intravenous administration of the compounds to mice, the inventivemolecules 120, 121, 140, 142, 143 and agomelatine presented higher C0and lower Clearance than agomelatine, highlighting the improvedpharmacokinetics of the inventive molecules.

According to the results after oral administration in mice, thecompounds and agomelatine showed a Tmax of 0.25 h, except compound 140(0.375 h). In addition, all the inventive compounds showed a Cmax higherthan agomelatine, being 3405, 6490, 5010, 7550, 8915 ng/ml for compounds120, 121, 140, 142 and 143, respectively, in comparison to 21.9 ng/mlfor agomelatine. In addition, the last measurable plasma concentration(AUClast) of the compounds was also higher in comparison to agomelatine.Finally, the bioavailability of the inventive compounds was considerablyhigher in comparison to agomelatine, being 44, 138, 71.3, 51.8 and 153%(120, 121, 140, 142 and 143) compared to 2.42% for agomelatine (Table6).

TABLE 6 IA2-76 (agomelatine) IA2-120 IA2-121 IA2-140 IA2-142 IA2-143 (A)INTRAVENOUS Mouse T_(1/2)(h) 0.149 0.237 0.178 0.296 0.275 0.187 C0(ng/ml) 811 1967 2052 1956 4129 2659 CL (ml/min/kg) 116 31.2 29.4 18.810.3 25.5 Rat T_(1/2)(h) 0.295 0.254 0.14 0.523 0.409 0.289 CL(ml/min/kg) 39.1 48.1 53.3 26 16.6 29.8 (B) ORAL Mouse Tmax(h) 0.25 0.250.25 0.375 0.25 0.25 Cmax(ng/ml) 21.9 3405 6490 5010 7550 8915AUClast(h*ng/ml) 30.3 2342 7865 6137 8285 9986 F (%) 2.42 44 138 71.351.8 153 Rat AUClast(h*ng/ml) 1025 554 3508 2435 10892 4049 F (%) 22.615.9 112 36.5 108 72.3t.

Pharmacokinetics (PK) in Rat—I.V. And Oral

PK tests were performed on Wistar-Han mice, using 4 animals per moleculetested, 2 animals for analysis of I.V. pharmacokinetics and 2 animalsfor analysis of oral PK. The study lasted for 2 weeks (includingacclimation time and study), in which the route of administration wasmade by injection into the caudal vein and oral gavage. The treatmentwas carried out in a single dose: I.V. group with dose of 1 mg/kg andOral group with dose of 10 mg/kg. The vehicle consisted of 5% DMSO, 30%PEG400 and 65% water. Clinical observations were made twice a day(morning and afternoon) in the pre-dose at the 08 time points defined inthe protocol. Blood collection was performed after euthanasia in thepre-dose animals at 08 defined time points and at 24 hours post-dose.The pharmacokinetic analysis parameters detected for Group IV were:half-life (t1/2), drug concentration at time zero (C0), last measurableplasma concentration (AUClast), area under the plasma concentrationcurve extrapolation percentage (AUC % ext), area under the plasmaconcentration curve extrapolation to infinity (AUCinf), volume ofdistribution (Vz), steady state volume of distribution (Vss), clearance(CL) and mean residence time (MRT). The parameters evaluated for theOral group were: bioavailability (F %), maximum concentration reached(Cmax), time to reach maximum plasma concentration (Tmax), lastmeasurable plasma concentration (AUClast), area under the plasmaconcentration curve extrapolation percentage (AUC % ext), area under theplasma concentration curve extrapolation to infinity (AUCinf), areaunder the plasma concentration curve extrapolation to infinity versusdose (AUCinf/Dose), half-Life (t1/2), and mean residence time (MRT).

Following intravenous administration in rats, it was observed that thehalf-lives of compounds 120, 121, 140, 142, 143 and agomelatine were0.254, 0.14, 0.523, 0.409, 0.289 and 0.295 h. And the clearance of thesame compounds was 48.1, 53.3, 26, 16.6, 29.8 and 39.1 ml/min/kg,respectively. Furthermore, after oral administration to rats, compounds120, 121, 140, 142, 143 and agomelatine showed a last measurable plasmaconcentration (AUClast) of 554, 3508, 2435, 10892, 4049 and 1025h*ng/ml, respectively, and bioavailability of 15, 9, 112, 36.5, 108,72.3 and 22.6%, respectively (Table 6). Thus, some of the inventivecompounds also demonstrated higher pharmacokinetic parameters thanagomelatine in Wistar-Han rats.

What is claimed is:
 1. A compound having the formula (II):

wherein X is an oxygen or sulfur atom; A represents a linear alkyl C₂₋₄group which may have one or more of its hydrogens replaced by an alkylgroup selected from the group consisting of methyl, ethyl, propyl, andisopropyl; R₁ represents an alkyl C₁₋₆ or alkenyl C₂₋₆ or alkynyl C₂₋₆or haloalkyl C₁₋₆ or cycloalkyl C₃₋₆ or C₁₋₂-alkyl cycloalkyl-C₃₋₆group; R₂ represents a hydrogen or an alkyl C₁₋₃ group; n is 0 or 1; andp is 1 or
 2. 2. The compound according to claim 1 wherein the compoundis selected from the group consisting of:—N-(2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazole-1-yl)ethyl)acetamide;and—N-(2-(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazole-1-yl)ethyl)acetamide.
 3. A process for obtaining the compound according to claim 1comprising: (a) reacting a compound of formula (IX)

with an tetraalkylorthocarbonate selected from the group consisting oftetramethylorthocarbonate and tetraethyl orthocarbonate, to obtain acompound of formula (X)

wherein R₂, “n” and “p” are as described for the compound of generalformula (II) (b) reacting the compound of formula (X) obtained in (a)with a deprotecting agent to obtain a compound of formula (XI)

(c) reacting the compound of formula (XI) obtained in (b) with acarboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula (V)

to obtain the compound of formula (IIa),

wherein R₁ is as described for the compound of formula (II) and X₁represents a bromine or chlorine atom; (d) reacting the compound (IX)with thiourea obtaining the compound of formula (XII)

(e) reacting the compound of formula (XII) obtained in (d) with analkylating agent obtaining the compound (XIII)

wherein “n” is as described for the compound of formula (II); (f)reacting the compound obtained in (e) with a deprotecting agent toobtain a compound of formula (XIV)

(g) reacting the compound of formula (XIV) with a carboxylic acidanhydride of formula (IV)

or with a carboxylic acid halide of formula (V)

to obtain the compound of formula (IIb):


4. A process for obtaining a compound of formula (IIa)

comprising: (a) reacting a compound of formula (IX)

with an tetraalkylorthocarbonate selected from the group consisting oftetramethylorthocarbonate and tetraethyl orthocarbonate, to obtain acompound of formula (X)

wherein R₂, n is 0 or 1; p is 1 or 2; (b) reacting the compound offormula (X) obtained in (a) with a deprotecting agent to obtain acompound of formula (XI)

(c) reacting the compound of formula (XI) obtained in (b) with acarboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula (V)

wherein R₁ is as described as set forth in claim 1 and X₁ represents abromine or chlorine atom.
 5. A process for obtaining a compound offormula (IIb)

comprising: (a) reacting a compound of formula (IX)

with thiourea obtaining the compound of formula (XII)

(b) reacting the compound of formula (XII) obtained in (a) with analkylating agent obtaining the compound of formula (XIII)

wherein n=0 or 1; (c) reacting the compound obtained in (b) with adeprotecting agent to obtain a compound of formula XIV:

(d) reacting the compound of formula (XIV) obtained in (c) with acarboxylic acid anhydride of formula (IV)

or with a carboxylic acid halide of formula (V).


6. A pharmaceutical composition comprising: a) at least one compound offormula (II):

wherein X corresponds to an oxygen or sulfur atom; A corresponds to alinear alkyl C₂₋₄ group, which may have one or more of its hydrogenssubstituted by an alkyl group selected from the group consisting ofmethyl, ethyl, propyl, and isopropyl; R₁ is an alkyl C₁₋₆, or alkenylC₂₋₆, or alkynyl C₂₋₆, or haloalkyl C₁₋₆, or cycloalkyl C₃₋₆, orC₁₋₂-alkyl-cycloalkyl C₃₋₆ group; R₂ is a hydrogen or a alkyl C₁₋₃group; n is 0 or 1; p is 1 or 2; and b) a pharmaceutically acceptablevehicle.
 7. The pharmaceutical composition according to claim 6, whereinthe compound of formula (II) is selected from the group consisting of:N-(2-(2-ethoxy-7,8-dihydro-1H-benzofuran[4,5-d]imidazole-1-yl)ethyl)acetamide; andN-(2—(2-methoxy-7,8-dihydro-1H-benzofuran[4,5-d] imidazole-1-yl)ethyl)acetamide.
 7. A method of using the compound according to claim 1comprising using said compound in the treatment of psychiatric disordersand/or sleep disorders.
 8. The method of using the compound according toclaim 7 wherein the compound is in the form of a pharmaceuticalcomposition comprising the compound of formula (II) and apharmaceutically acceptable vehicle.
 9. A method of treating psychiatricdisorders and/or sleep disorders coprising administering to a mammal inneed thereof a therapeutically effective amount of the compound ofclaim
 1. 10. A method of treating psychiatric disorders and/or sleepdisorders coprising administering to a mammal in need thereof atherapeutically effective amount of the pharmaceutical composition ofclaim 6.